U.S. patent application number 15/212279 was filed with the patent office on 2017-01-19 for compositions and agents against hepatitis b virus and uses thereof.
The applicant listed for this patent is Arcturus Therapeutics, Inc.. Invention is credited to Padmanabh Chivukula, Christine Esau, Pattraranee Limphong, Kiyoshi Tachikawa.
Application Number | 20170016000 15/212279 |
Document ID | / |
Family ID | 57775056 |
Filed Date | 2017-01-19 |
United States Patent
Application |
20170016000 |
Kind Code |
A1 |
Limphong; Pattraranee ; et
al. |
January 19, 2017 |
COMPOSITIONS AND AGENTS AGAINST HEPATITIS B VIRUS AND USES
THEREOF
Abstract
This invention encompasses compounds and compositions useful in
methods for medical therapy, in general, for inhibiting Hepatitis B
virus in a subject. The compounds have a first strand and a second
strand, each of the strands being 19-29 monomers in length, the
monomers comprising UNA monomers and nucleic acid monomers, and the
compounds are targeted to a sequence of an HBV genome.
Inventors: |
Limphong; Pattraranee; (San
Diego, CA) ; Tachikawa; Kiyoshi; (San Diego, CA)
; Esau; Christine; (San Diego, CA) ; Chivukula;
Padmanabh; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Arcturus Therapeutics, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
57775056 |
Appl. No.: |
15/212279 |
Filed: |
July 17, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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62193997 |
Jul 17, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C12N 2310/323 20130101;
C12N 15/1131 20130101; C12N 2310/14 20130101; C12N 2310/344
20130101; A61P 31/20 20180101; A61P 1/16 20180101 |
International
Class: |
C12N 15/113 20060101
C12N015/113 |
Claims
1. A compound comprising a first strand and a second strand, each
of the strands being 19-29 monomers in length, the monomers
comprising UNA monomers and nucleic acid monomers, wherein the
compound has a duplex region of from 14 to 29 contiguous monomers
in length, wherein the first strand is a passenger strand for RNA
interference and the second strand is a guide strand for RNA
interference, and wherein the compound comprises a sequence of
bases targeted to inhibit expression of an HBV genome.
2. The compound of claim 1, wherein the compound contains one to
seven UNA monomers.
3. The compound of claim 1, wherein the compound contains a UNA
monomer at the 1-end (5' end for non-UNA) of the first strand, a
UNA monomer at the 3-end (3' end for non-UNA) of the first strand,
and a UNA monomer at the second position from the 5' end of the
second strand.
4. The compound of claim 1, wherein the compound contains a UNA
monomer at any one or more of positions 2 to 8 from the 5' end of
the second strand.
5. The compound of claim 1, wherein the sequence of bases is
selected from the sense, antisense or sense-antisense pairs of the
following, and substituted forms thereof: TABLE-US-00035 SEQ SEQ
REF NO ID POS ID Sense (5'-3') NO Antisense (5'-3') 1578 867
UGUGCACUUCGCUUCACCU 908 AGGUGAAGCGAAGUGCACA 1777 875
GAGGCUGUAGGCAUAAAUU 916 AAUUUAUGCCUACAGCCUC 1581 869
GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 380 887
UGUCUGCGGCGUUUUAUCA 928 UGAUAAAACGCCGCAGACA 1576 899
CGUGUGCACUUCGCUUCAC 940 GUGAAGCGAAGUGCACACG 1780 877
GCUGUAGGCAUAAAUUGGU 918 ACCAAUUUAUGCCUACAGC 1781 878
CUGUAGGCAUAAAUUGGUC 919 GACCAAUUUAUGCCUACAG 1782 879
UGUAGGCAUAAAUUGGUCU 920 AGACCAAUUUAUGCCUACA 376 885
GAUGUGUCUGCGGCGUUUU 926 AAAACGCCGCAGACACAUC 378 886
UGUGUCUGCGGCGUUUUAU 927 AUAAAACGCCGCAGACACA 411 893
UCCUGCUGCUAUGCCUCAU 934 AUGAGGCAUAGCAGCAGGA 413 895
CUGCUGCUAUGCCUCAUCU 936 AGAUGAGGCAUAGCAGCAG 1580 900
UGCACUUCGCUUCACCUCU 941 AGAGGUGAAGCGAAGUGCA 1581 869
GCACUUCGCUUCACCUCUG 910 CAGAGGUGAAGCGAAGUGC 1575 865
CCGUGUGCACUUCGCUUCA 906 UGAAGCGAAGUGCACACGG 1818 888
AACUUUUUCACCUCUGCCU 929 AGGCAGAGGUGAAAAAGUU
6. The compound of claim 1, wherein the compound comprises one of
the following pairs: SEQ ID NO:987 and 988; SEQ ID NO:993 and 994;
SEQ ID NO:999 and 1000; SEQ ID NO:1005 and 1006; SEQ ID NO:1009 and
1010; SEQ ID NO:1011 and 1012; SEQ ID NO:1013 and 1014; SEQ ID
NO:1015 and 1016; SEQ ID NO:969 and 970; SEQ ID NO:971 and 972; SEQ
ID NO:973 and 974; SEQ ID NO:977 and 978; SEQ ID NO:981 and 982;
SEQ ID NO:989 and 990; SEQ ID NO:997 and 998; and SEQ ID NO:999 and
1000.
7. The compound of claim 1, wherein the compound comprises one of
the following pairs: SEQ ID NO:1145 and 1146; SEQ ID NO:1175 and
1176; SEQ ID NO:1149 and 1150; SEQ ID NO:1163 and 1164; SEQ ID
NO:1165 and 1166; SEQ ID NO:1167 and 1168; SEQ ID NO:1169 and 1170;
SEQ ID NO:1153 and 1154; SEQ ID NO:1155 and 1156; SEQ ID NO:1157
and 1158; SEQ ID NO:1160 and 1161; SEQ ID NO:1159 and 1160; SEQ ID
NO:1147 and 1148; and SEQ ID NO:1151 and 1152.
8. The compound of claim 1, wherein the compound has a 3' overhang
comprising one or more UNA monomers, natural nucleotides,
non-natural nucleotides, modified nucleotides, or
chemically-modified nucleotides, and combinations thereof.
9. The compound of claim 1, wherein the compound has a 3' overhang
comprising one or more deoxythymidine nucleotides, 2'-O-methyl
nucleotides, inverted abasic monomers, inverted thymidine monomers,
L-thymidine monomers, or glyceryl nucleotides.
10. The compound of claim 1, wherein one or more of the nucleic
acid monomers is a non-natural nucleotide, a modified nucleotide,
or a chemically-modified nucleotide.
11. The compound of claim 1, wherein each nucleic acid monomer has
a 2'-O-methyl group.
12. The compound of claim 1, wherein the compound contains from one
to eight nucleic acid monomers modified with a 2'-O-methyl group in
the first strand and from one to eleven nucleic acid monomers
modified with a 2'-O-methyl group in the second strand.
13. The compound of claim 1, wherein the compound contains one or
more 2'-methoxyethoxy nucleotides.
14. The compound of claim 1, wherein the compound contains one or
more 2'-deoxy-2'-fluoro ribonucleotides.
15. The compound of claim 1, wherein the compound does not contain
fluorine.
16. The compound of claim 1, wherein one or more of three monomers
at each end of each strand is connected by a phosphorothioate, a
chiral phosphorothioate, or a phosphorodithioate linkage.
17. The compound of claim 1, wherein the compound has one
phosphorothioate linkage between two monomers at the 5' end of the
first strand, one phosphorothioate linkage between two monomers at
the 3' end of the first strand, one phosphorothioate linkage
between monomers at the second and third positions from the 3' end
of the first strand, and one phosphorothioate linkage between two
monomers at the 3' end of the second strand.
18. The compound of claim 1, wherein the compound is conjugated to
a delivery moiety.
19. The compound of claim 1, wherein the compound is conjugated to
a delivery moiety that binds to a glycoprotein receptor.
20. The compound of claim 1, wherein the compound is conjugated to
a delivery moiety that binds to a glycoprotein receptor, wherein
the delivery moiety comprises a galactose, a galactosamine, or a
N-acetylgalactosamine.
21. The compound of claim 1, wherein the compound is conjugated to
a GalNAc delivery moiety.
22. The compound of claim 1, wherein the compound is conjugated to
a cholesterol delivery moiety.
23. The compound of claim 1, wherein the compound is conjugated to
a delivery moiety at an end of the compound and has increased
uptake in the liver as compared to an unconjugated compound.
24. A lipid nanoparticle-oligomer compound comprising one or more
compounds of claim 1 attached to the lipid nanoparticle.
25. A composition comprising one or more compounds of claim 1 and a
pharmaceutically acceptable carrier.
26. The composition of claim 25, wherein the carrier comprises
lipid nanoparticles or liposomes.
27. A composition comprising a first compound of claim 1 targeted
to a conserved region of HBV transcripts for genes X, C, P and S, a
second compound of claim 1 targeted to inhibit HBsAg, a third
compound of claim 1 targeted to a conserved region of HBV
transcripts for genes X, C and S, and a pharmaceutically acceptable
carrier.
28. The composition of claim 27, wherein the carrier comprises
lipid nanoparticles or liposomes.
29. A composition comprising one or more compounds having reference
positions from any of positions 1525 to 1582, 374 to 414, 1776 to
1782, 244 to 256, and 1818 to 1866.
30. The composition of claim 29, comprising a compound having a
reference position from 1525 to 1582, a compound having a reference
position from 374 to 414, and a compound having a reference
position from 1776 to 1782.
31. A composition comprising a triad of compounds, wherein the
triad is selected from the following: the first compound comprises
SEQ ID NO:867 and 908, the second compound comprises SEQ ID NO:887
and 928, and the third compound comprises SEQ ID NO:875 and 916;
the first compound comprises SEQ ID NO:899 and 940, the second
compound comprises SEQ ID NO:887 and 928, and the third compound
comprises SEQ ID NO:875 and 916; the first compound comprises SEQ
ID NO:865 and 906, the second compound comprises SEQ ID NO:887 and
928, and the third compound comprises SEQ ID NO:875 and 916; the
first compound comprises SEQ ID NO:869 and 910, the second compound
comprises SEQ ID NO:887 and 928, and the third compound comprises
SEQ ID NO:875 and 916; the first compound comprises SEQ ID NO:867
and 908, the second compound comprises SEQ ID NO:885 and 926, and
the third compound comprises SEQ ID NO:875 and 916; and the first
compound comprises SEQ ID NO:867 and 908, the second compound
comprises SEQ ID NO:887 and 928, and the third compound comprises
SEQ ID NO:877 and 918.
32. An siRNA comprising nucleotides, wherein the siRNA is targeted
to HBV and has a sequence selected from the sense, antisense or
sense-antisense pairs of the following, and substituted forms
thereof: TABLE-US-00036 SEQ SEQ REF ID ID POS NO Sense (5'-3') NO
Antisense (5'-3') 1777 875 GAGGCUGUAGGCAUAAAUU 916
AAUUUAUGCCUACAGCCUC 1581 869 GCACUUCGCUUCACCUCUG 910
CAGAGGUGAAGCGAAGUGC 380 887 UGUCUGCGGCGUUUUAUCA 928
UGAUAAAACGCCGCAGACA 1576 899 CGUGUGCACUUCGCUUCAC 940
GUGAAGCGAAGUGCACACG 1780 877 GCUGUAGGCAUAAAUUGGU 918
ACCAAUUUAUGCCUACAGC 1781 878 CUGUAGGCAUAAAUUGGUC 919
GACCAAUUUAUGCCUACAG 1782 879 UGUAGGCAUAAAUUGGUCU 920
AGACCAAUUUAUGCCUACA 376 885 GAUGUGUCUGCGGCGUUUU 926
AAAACGCCGCAGACACAUC 413 895 CUGCUGCUAUGCCUCAUCU 936
AGAUGAGGCAUAGCAGCAG 1580 900 UGCACUUCGCUUCACCUCU 941
AGAGGUGAAGCGAAGUGCA 1818 888 AACUUUUUCACCUCUGCCU 929
AGGCAGAGGUGAAAAAGUU
33. A method for preventing, ameliorating or treating a disease or
condition associated with HBV infection in a subject in need, the
method comprising administering to the subject an effective amount
of a composition of claim 25.
34. The method of claim 33, wherein the administration of the
composition reduces HBV viral titer in the subject.
35. The method of claim 33, wherein the subject has been diagnosed
with a disease associated with Hepatitis B virus infection.
36. The method of claim 33, wherein the subject has been diagnosed
with liver disease.
37. A method for inhibiting the replication, maturation, growth, or
transmission of a Hepatitis B virus in a subject in need, the
method comprising administering to the subject an effective amount
of a composition of claim 25.
38. The method of claim 37, wherein the administration of the
composition reduces serum concentration of HBsAg in the
subject.
39. The method of claim 37, wherein the administration of the
composition reduces serum concentration of HBsAg in the subject by
2-log.sub.10-fold.
40. The method of claim 37, wherein the administration of the
composition reduces serum concentration of HBsAg in the subject by
2-log.sub.10-fold for at least 7 days.
41. The method of claim 37, wherein the administration of the
composition reduces HBeAg in the subject.
42. The method of claim 37, wherein the administration of the
composition reduces HBV DNA in the subject.
43. A method for inhibiting expression of a Hepatitis B virus
polynucleotide in a subject in need, the method comprising
administering to the subject a composition of claim 25.
Description
SEQUENCE LISTING
[0001] This application includes a Sequence Listing submitted
electronically as an ASCII file named ARC1410US_SL.txt.
BACKGROUND OF THE INVENTION
[0002] Hepatitis B is a liver disease that results from infection
with the Hepatitis B virus (HBV). Its severity can be from a mild
illness lasting a few weeks, to a serious, lifelong illness.
Hepatitis B can be either acute or chronic. Acute Hepatitis B virus
infection is a short-term illness that may lead to chronic
infection. Chronic Hepatitis B virus infection is a long-term
illness that can result in long-term health problems, such as
cirrhosis of the liver, liver cancer, and death.
[0003] Hepatitis B is usually spread through transfer of a body
fluid by sexual contact with an infected person, or through sharing
needles for drug-injection. It can also be passed from an infected
mother to her baby at birth. In endemic areas, Hepatitis B is most
often spread from mother to child at birth, or by exposure to
infected blood, especially from an infected child to an uninfected
child during the first 5 years of life.
[0004] According to the latest WHO estimates, as many as 240
million people are chronically infected with Hepatitis B, defined
as Hepatitis B surface antigen positive for at least 6 months.
Approximately 780,000 persons die each year from Hepatitis B
infection.
[0005] There is no specific treatment for acute hepatitis B.
Chronic hepatitis B infection can be treated with drugs, including
oral antiviral agents. WHO recommends the use of oral treatments
such as tenofovir or entecavir. In most people, the treatment
suppresses replication of the virus, but does not cure hepatitis B
infection. Liver cancer progresses rapidly, and treatment options
are limited. Surgery and chemotherapy, or liver transplantation can
prolong life for up to a few years.
[0006] Laboratory diagnosis of hepatitis B infection can be done by
detecting the hepatitis B surface antigen HBsAg. Acute hepatitis B
virus infection is characterized by the presence of HBsAg and
immunoglobulin M (IgM) antibody to the core antigen, HBcAg. During
the initial phase of infection, patients are also seropositive for
hepatitis B e-antigen (HBeAg). HBeAg is usually a marker of high
levels of replication of the virus. The presence of HBeAg indicates
that the blood and body fluids of the infected individual are
highly contagious. Chronic infection is characterized by the
persistence of HBsAg for at least 6 months, with or without
concurrent HBeAg. Persistence of HBsAg is the principal marker of
risk for developing chronic liver disease and liver cancer later in
life.
[0007] HBV is a member of the hepadnavirus family. The virus
particles, which can infect liver cells, are 30-42 nm in diameter
and have an outer envelope and an icosahedral nucleocapsid core.
The nucleocapsid encloses the viral DNA, and a DNA polymerase that
can have reverse transcriptase activity. The outer envelope
contains proteins that can be involved in viral binding and entry
into cells.
[0008] In general, HBV has four identified genes, C, P, S, and X.
Gene C codes for a core protein, HBcAg. An extracellular protein
HBeAg is processed from a pre-core protein. A DNA polymerase is
encoded by gene P. Gene S codes for the small surface antigen
HBsAg, which is one of three polypeptide surface proteins: large,
middle, and small. Gene X may be associated with development of
liver cancer.
[0009] HBV is a pararetrovirus, which is a non-retrovirus that uses
reverse transcription in the replication process. The virus can
enter the cell and multiply using RNA made by a host process. The
viral genomic DNA can be transferred to the cell nucleus, acted
upon by viral polymerase, and provide transcription of four viral
mRNAs by host RNA polymerase. A large viral mRNA is used to make
the new copies of the genome by reverse transcription, and to make
the core protein and the viral DNA polymerase. The viral mRNAs are
further processed to form new virus particles.
[0010] HBV can be described by four major serotypes based on
epitopes presented by envelope proteins: adr, adw, ayr, ayw. HBV
has been identified with eight genotypes, A-H, as well as
subgenotypes. The genotypes can have distinct geographical
distribution, and are used in tracking evolution and transmission
of the virus.
[0011] What is needed are compositions and methods for treatment of
Hepatitis B.
[0012] There is an urgent need for new methods and compositions for
ameliorating or treating Hepatitis B infection.
BRIEF SUMMARY
[0013] This invention relates to the fields of biopharmaceuticals
and therapeutics composed of oligomers for gene silencing. More
particularly, this invention relates to structures, compositions
and methods for therapeutic oligomers directed against Hepatitis B
virus.
[0014] This invention provides novel molecules to be used as
therapeutic agents against Hepatitis B infection. The molecules of
this invention can be used as active pharmaceutical ingredients in
compositions for ameliorating, preventing or treating Hepatitis B
infection.
[0015] Molecules of this invention for treating Hepatitis B
infection may act against any of the replication, maturation,
growth, or transmission modalities of the Hepatitis B virus. By
preventing the Hepatitis B virus from carrying out any one or more
of its processes, the molecules of this invention can be used for
ameliorating or treating Hepatitis B infection.
[0016] Embodiments of this invention can provide molecules having
one or more properties that advantageously provide enhanced
effectiveness against HBV, as well as compositions or formulations
for therapeutic agents against Hepatitis B infection, which can
provide clinical agents. The properties of the molecules of this
invention arise according to their structure, and the molecular
structure in its entirety, as a whole, can provide significant
benefits and properties.
[0017] The active agents of this invention include oligomeric
molecules that can inhibit expression of an HBV genome. Oligomers
of this invention can provide potent action against HBV infection
in a subject by silencing expression of an HBV genome.
[0018] In some embodiments, a wide range of novel molecules are
provided, which can incorporate one or more linker groups. The
linker groups can be attached in a chain in the molecule. Each
linker group can also be attached to a nucleobase.
[0019] In some aspects, a linker group can be a monomer. Monomers
can be attached to form a chain molecule. In a chain molecule of
this invention, a linker group monomer can be attached at any point
in the chain.
[0020] In certain aspects, linker group monomers can be attached in
a chain molecule of this invention so that the linker group
monomers reside near the ends of the chain. The ends of the chain
molecule can be formed by linker group monomers.
[0021] In further aspects, the linker groups of a chain molecule
can each be attached to a nucleobase. The presence of nucleobases
in the chain molecule can provide a sequence of nucleobases.
[0022] In certain embodiments, this invention provides oligomer
molecules having chain structures that incorporate novel
combinations of the linker group monomers, along with certain
natural nucleotides, or non-natural nucleotides, or modified
nucleotides, or chemically-modified nucleotides.
[0023] The oligomer molecules of this invention can display a
sequence of nucleobases that is targeted to a component of the HBV
genome.
[0024] In additional aspects, this invention provides therapeutics
for preventing, ameliorating, or treating a disease caused by
Hepatitis B infection. An active compound or molecule of this
invention may be used in the prevention or treatment of a viral
infection caused by Hepatitis B virus.
[0025] This invention provides structures, methods and compositions
for oligomeric agents that incorporate the linker group monomers.
The oligomeric molecules of this invention can be used as active
agents in formulations for gene silencing therapeutics targeted to
HBV.
[0026] Embodiments of this invention include the following:
[0027] A compound comprising a first strand and a second strand,
each of the strands being 19-29 monomers in length, the monomers
comprising UNA monomers and nucleic acid monomers, wherein the
compound has a duplex region of from 14 to 29 contiguous monomers
in length, wherein the first strand is a passenger strand for RNA
interference and the second strand is a guide strand for RNA
interference, and wherein the compound comprises a sequence of
bases targeted to inhibit expression of an HBV genome. The compound
may contain from one to seven UNA monomers.
[0028] In some embodiments, the compound may contain a UNA monomer
at the 1-end (5' end for non-UNA) of the first strand, a UNA
monomer at the 3-end (3' end for non-UNA) of the first strand, and
a UNA monomer at the second position from the 5' end of the second
strand. A compound can contain a UNA monomer at any one or more of
positions 2 to 8 from the 5' end of the second strand.
[0029] In certain embodiments, a compound may have a 3' overhang
with one or more UNA monomers, natural nucleotides, non-natural
nucleotides, modified nucleotides, or chemically-modified
nucleotides, or combinations thereof. The 3' overhang can have one
or more deoxythymidine nucleotides, 2'-O-methyl nucleotides,
inverted abasic monomers, inverted thymidine monomers, L-thymidine
monomers, or glyceryl nucleotides.
[0030] In some aspects, a compound may have one or more nucleic
acid monomers that is a non-natural nucleotide, a modified
nucleotide, or a chemically-modified nucleotide. A compound may
have one or more monomers connected by a phosphorothioate, a chiral
phosphorothioate, or a phosphorodithioate linkage.
[0031] In further aspects, a compound may be conjugated to a
delivery moiety, such as, for example, a moiety that binds to a
glycoprotein receptor, a galactose, a galactosamine, a
N-acetylgalactosamine, a GalNAc group, or a cholesterol delivery
moiety. A compound may be conjugated to a delivery moiety and have
increased uptake in the liver as compared to an unconjugated
compound.
[0032] This invention includes lipid nanoparticle-oligomer
compounds, in which one or more compounds are attached to a lipid
nanoparticle.
[0033] A composition of this disclosure can include one or more
compounds and a pharmaceutically acceptable carrier. The carrier
may be lipid nanoparticles or liposomes.
[0034] A composition of this disclosure may contain a first
compound targeted to a conserved region of HBV transcripts for
genes X, C, P and S, a second compound targeted to inhibit HBsAg, a
third compound targeted to a conserved region of HBV transcripts
for genes X, C and S, and a pharmaceutically acceptable
carrier.
[0035] Embodiments of this invention include compositions
containing one or more compounds having reference positions from
any of positions 1525 to 1582, 374 to 414, 1776 to 1782, 244 to
256, and 1818 to 1866. In certain embodiments, a composition may
include a compound having a reference position from 1525 to 1582, a
compound having a reference position from 374 to 414, and a
compound having a reference position from 1776 to 1782.
[0036] Embodiments of this invention further contemplate methods
for preventing, ameliorating or treating a disease or condition
associated with HBV infection in a subject in need, by
administering to the subject an effective amount of a composition
above. The administration of the composition can reduce HBV viral
titer in the subject. A subject may have been diagnosed with a
disease associated with Hepatitis B virus infection, for example, a
liver disease.
[0037] This invention includes methods for inhibiting the
replication, maturation, growth, or transmission of a Hepatitis B
virus in a subject in need, by administering to the subject an
effective amount of a composition above. The composition may reduce
serum concentration of HBsAg in the subject. In some embodiments,
the administration of the composition may reduce serum
concentration of HBsAg in the subject by 2-log.sub.10-fold, or by
2-log.sub.10-fold for at least 7 days. In certain embodiments, the
administration of the composition can reduce HBeAg in the subject,
or HBV DNA in the subject.
[0038] This invention also contemplates methods for inhibiting
expression of a Hepatitis B virus polynucleotide in a subject in
need, by administering to the subject a composition above, as well
as the use of a composition above for preventing, ameliorating or
treating a disease or condition associated with Hepatitis B
infection in a subject in need.
[0039] In some aspects, this disclosure includes compositions for
use in medical therapy, or for use in the treatment of the human or
animal body. In certain aspects, this invention includes the use of
a composition for preparing or manufacturing a medicament for
preventing, ameliorating or treating a disease or condition
associated with Hepatitis B infection in a subject in need.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1 shows a map of HBV protein coding regions and
selected transcripts for a reference genome. Nucleotide position
1/3221 is designated at the top. Further designations are as
follows: pre-S1, large HBsAg; pre-S2, medium HBsAg; S, HBsAg; P,
polymerase; X, HBx protein; pre-C, pre-core/HBeAg; C, HB core Ag.
The 2.4 kb, 2.1 kb, and 0.7 kb transcripts coding for the
pre-S1/pre-S2/S, as well as the transcript coding the X protein are
shown. The pre-Core/HBeAg protein is generated from a long, 3.5 kb
transcript (not shown) originating at position .about.1700, while
the core and polymerase proteins and the pre-genomic RNA used as a
template for viral replication are generated from a .about.200 nt
shorter transcript. The ranges of reference positions for certain
UNA oligomers, designated UNA oligomer 1, UNA oligomer 2, and UNA
oligomer 3, are shown.
[0041] FIG. 2 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. The UNA oligomers of this invention exhibited profound
reduction of HBV serum infection parameters in vivo. In this study,
the UNA oligomers were contained in lipid nanoparticle
formulations,-1 and -2, and an ascending dose was used. The UNA
oligomers were formulated in lipid nanoparticles and injected
intravenously into HBV-infected Phoenix Bio (PXB) mice containing
human hepatocytes (70%). Treatment with both UNA oligomer 1576 and
a UNA oligomer triad composition (1576, 380, 177) caused a rapid
and sustained reduction in viral endpoint serum HBsAg.
[0042] FIG. 3 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomer triad (1576, 380, 1777)
caused a rapid and sustained reduction in viral endpoint serum
HBsAg. The dose-dependent response in vivo shows a pharmacological
effect of the UNA oligomer composition. The study used an ascending
dose in which mice were administered every 4 days, up to day 40,
and viral endpoints were monitored every 4 days through day 44.
[0043] FIG. 4 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomer triad (1576, 380, 1777)
caused a rapid and sustained reduction in viral endpoint serum
HBeAg. The dose-dependent response in vivo shows a pharmacological
effect of the UNA oligomer composition. The study used an ascending
dose in which mice were administered every 4 days, up to day 40,
and viral endpoints were monitored every 4 days through day 44.
[0044] FIG. 5 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomer triad (1576, 380, 1777)
caused a rapid and sustained reduction in viral endpoint serum HBV
DNA. The dose-dependent response in vivo shows a pharmacological
effect of the UNA oligomer composition. The study used an ascending
dose in which mice were administered every 4 days, up to day 40,
and viral endpoints were monitored every 4 days through day 44.
[0045] FIG. 6 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a
rapid and sustained reduction in viral endpoint serum HBsAg.
[0046] FIG. 7 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a
rapid and sustained reduction in viral endpoint serum HBeAg.
[0047] FIG. 8 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with UNA oligomers 1777, 380 and 1578 caused a
rapid and sustained reduction in viral endpoint serum HBV DNA.
[0048] FIG. 9 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with a UNA oligomer triad composition (1578,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBsAg. The dose-dependent response in vivo shows a
pharmacological effect of the UNA oligomer composition.
[0049] FIG. 10 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with a UNA oligomer triad composition (1578,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBeAg. The dose-dependent response in vivo shows a
pharmacological effect of the UNA oligomer composition.
[0050] FIG. 11 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in a humanized PXB Mouse model of HBV
infection. Treatment with a UNA oligomer triad composition (1578,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBV DNA. The dose-dependent response in vivo shows a
pharmacological effect of the UNA oligomer composition.
[0051] FIG. 12 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers of this invention exhibited profound reduction of HBV
serum infection parameters in vivo. In general, the AAV-HBV mouse
model is a robust model for investigating HBV infection. The UNA
oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver. The
study used an ascending dose, and serum viral endpoints were
monitored 15 days before, and at least 22 days after treatment.
Treatment with each of UNA oligomers 380, 1777, and 1576 caused a
rapid and sustained reduction in viral endpoint serum HBsAg.
[0052] FIG. 13 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver.
Treatment with each of UNA oligomers 380, 1777, and 1576, as well
as the UNA oligomer triad composition of the same compounds (1576,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBeAg. This head-to-head comparison shows that the triad
composition provided surprisingly increased potency throughout the
duration of the effect, relative to the individual oligomers.
[0053] FIG. 14 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver.
Treatment with each of UNA oligomers 380, 1777, and 1576 caused a
rapid and sustained reduction in viral endpoint serum HBV DNA.
[0054] FIG. 15 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver. The
study was an ascending dose design in which mice were treated with
3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day 8,
and serum viral endpoints were monitored up to day 12 after
treatment. Treatment with the UNA oligomer triad composition (1777,
380, 1578) caused a rapid and sustained reduction in viral endpoint
serum HBsAg. The dose-dependent response in vivo shows a
pharmacological effect of the UNA oligomer composition.
[0055] FIG. 16 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver.
Treatment with each of UNA oligomers 1578 and 1575 caused a rapid
and sustained reduction in viral endpoint serum HBsAg.
[0056] FIG. 17 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver.
Treatment with each of UNA oligomers 1578 and 1575 caused a rapid
and sustained reduction in viral endpoint serum HBeAg.
[0057] FIG. 18 shows HBV inhibitory effect in vivo for UNA
oligomers, observed in an AAV-HBV mouse model of HBV infection. The
UNA oligomers were formulated in lipid nanoparticles and injected
intravenously into C57Bl/6 mice with active HBV replication after
AAV-mediated delivery of a recombinant HBV genome to the liver.
Treatment with each of UNA oligomers 1578 and 1575 caused a rapid
and sustained reduction in viral endpoint serum HBV DNA.
DETAILED DESCRIPTION OF THE INVENTION
[0058] This invention provides a range of novel agents and
compositions to be used as therapeutics against Hepatitis B
infection. Molecules of this invention can be used as active
pharmaceutical ingredients in compositions for ameliorating,
preventing or treating Hepatitis B infection.
[0059] The galenic molecules of this invention can prevent
Hepatitis B virus from carrying out one or more of its processes.
Molecules of this invention can be used for ameliorating or
treating Hepatitis B infection, and may act against any of the
replication, maturation, growth, or transmission modes of the
Hepatitis B virus.
[0060] Novel agents of this invention include oligomeric molecules
that inhibit expression of an HBV genome.
[0061] Embodiments of this invention can provide extraordinary and
surprisingly enhanced efficacy against HBV infection in a subject
by attacking all portions of the HBV genome. More particularly,
agents and compositions of this invention can simultaneously
inhibit all identified genes of HBV: C, P, S, and X. Thus, the
compounds and compositions of this disclosure can inhibit the small
surface antigen HBsAg, as well as the extracellular protein HBeAg,
in addition to X protein and viral polymerase.
[0062] The properties of the compounds of this invention arise
according to their molecular structure, and the structure of the
molecule in its entirety, as a whole, can provide significant
benefits based on those properties. Embodiments of this invention
can provide molecules having one or more properties that
advantageously provide enhanced effectiveness against HBV, as well
as compositions or formulations for therapeutic agents against
Hepatitis B infection, which can provide clinical agents.
[0063] A wide range of novel molecules are provided, each of which
can incorporate specialized linker groups. The linker groups can be
attached in a chain in the molecule. Each linker group can also be
attached to a nucleobase.
[0064] In some aspects, a linker group can be a monomer. Monomers
can be attached to form a chain molecule. In a chain molecule of
this invention, a linker group monomer can be attached at any point
in the chain.
[0065] In certain aspects, linker group monomers can be attached in
a chain molecule of this invention so that the linker group
monomers reside near the ends of the chain. The ends of the chain
molecule can be formed by linker group monomers.
[0066] As used herein, a chain molecule can also be referred to as
an oligomer.
[0067] In further aspects, the linker groups of a chain molecule
can each be attached to a nucleobase. The presence of nucleobases
in the chain molecule can provide a sequence of nucleobases.
[0068] In certain embodiments, this invention provides oligomer
molecules having chain structures that incorporate novel
combinations of the linker group monomers, along with certain
natural nucleotides, or non-natural nucleotides, or modified
nucleotides, or chemically-modified nucleotides.
[0069] The oligomer molecules of this invention can display a
sequence of nucleobases that is targeted to a component of an HBV
genome. In some embodiments, an oligomer can be targeted to a
portion of the HBV genome that is conserved, or highly conserved,
among a number of known HBV genomic sequences.
[0070] In some aspects, this invention provides active oligomer
molecules that correspond to, or are complementary to at least a
fragment of an HBV nucleic acid molecule, and that decrease
expression of at least such a fragment present in a cell. In some
embodiments, the active oligomer molecule can be
double-stranded.
[0071] Without wishing to be bound by any one particular theory, it
is believed that a cellular pathway may use active oligomers of
this invention to be sequence-specific regulators in an RNA
interference pathway. The active oligomers may bind to the
RNA-induced silencing complex (RISC complex), where a sense strand,
also referred to as the passenger strand, and an antisense strand,
also referred to as the guide strand, can be unwound, and the
antisense strand complexed in the RISC complex. The guide strand
can bind to a complementary sequence to which it was targeted, for
example, a target sequence in an mRNA, which can be subsequently
cleaved, resulting in inactivation of the nucleic acid molecule
containing the target sequence. As a result, the expression of mRNA
containing the target sequence can be reduced.
[0072] In some embodiments, an oligomeric molecule may be attached
to a delivery moiety. Examples of delivery moieties include
glycoprotein receptors, galactoses, galactosamines,
N-acetylgalactosamines, GalNAc groups, cholesterols, sterols,
phytosterols, steroids, zoosterols, lanosterols, stigmastanols,
dihydrolanosterols, zymosterols, zymostenols, desmosterols, and
7-dehydrocholesterol s.
[0073] In additional aspects, this invention provides therapeutics
for preventing, ameliorating, or treating a disease caused by
Hepatitis B infection. An active compound or molecule of this
invention may be used in the prevention or treatment of a viral
infection caused by Hepatitis B virus.
[0074] This invention provides structures, methods and compositions
for oligomeric agents that incorporate the linker group monomers.
The oligomeric molecules of this invention can be used as active
agents in formulations for gene silencing therapeutics targeted to
HBV.
[0075] This invention provides a range of molecules that are useful
for providing therapeutic effects because of their activity in
regulating expression of a gene. The molecules of this invention
are structured to provide gene regulating or silencing activity in
vitro and in vivo.
[0076] Embodiments of this invention can provide molecules for use
as therapeutic agents against Hepatitis B infection. The molecules
can be used as active pharmaceutical ingredients in compositions
for ameliorating, preventing or treating Hepatitis B infection.
[0077] In certain embodiments, an active molecule can be structured
as an oligomer composed of monomers. The oligomeric structures of
this invention may contain one or more linker group monomers, along
with certain nucleotides.
[0078] Modalities of Action
[0079] Molecules of this invention for treating Hepatitis B
infection may act against any of the replication, maturation,
growth, or transmission modalities of the Hepatitis B virus. By
preventing the Hepatitis B virus from carrying out any one or more
of its normal processes, the molecules of this invention can be
used for ameliorating or treating Hepatitis B infection.
[0080] This invention can provide unexpectedly advantageous
efficacy against HBV infection in a subject by simultaneously
modulating all portions of the HBV genome.
[0081] In some embodiments, inventive UNA oligomeric agents and
compositions of this disclosure can inhibit expression of each of
the HBV genes C, P, S, and X.
[0082] In some aspects, inventive UNA oligomeric agents and
compositions of this disclosure can simultaneously inhibit
expression of all genes of HBV, including genes C, P, S, and X.
[0083] In particular aspects, inventive UNA oligomeric compositions
of this disclosure can simultaneously inhibit expression of
multiple genes of HBV, such as genes P and C, or P and S, or P and
X.
[0084] In further aspects, inventive UNA oligomeric compositions of
this disclosure can simultaneously inhibit expression of multiple
genes of HBV, such as genes P, S and C, or P, X and S, or P, C and
X.
[0085] In certain aspects, the compounds of this invention can
inhibit the small surface antigen HBsAg in vivo, regardless of the
genomic source of HBsAg in the subject.
[0086] In further aspects, compounds and compositions of this
invention can inhibit the HBV extracellular protein HBeAg, the X
protein, and HBV viral polymerase.
[0087] In some aspects, a therapeutic molecule of this invention
can be active in preventing or inhibiting a step of the replication
cycle of hepatitis B virus.
[0088] Viral components of HBV can include a nucleocapsid, fully or
partially double stranded DNA (relaxed circular, rcDNA), a
polymerase, surface antigens, core proteins, a regulatory
X-protein, and secreted proteins.
[0089] In some embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting attachment of
viral components to cell-associated proteoglycans.
[0090] Certain embodiments of this invention provide a therapeutic
molecule that can be active in preventing or inhibiting binding of
a viral component to a hepatocyte receptor.
[0091] In further embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting entry of a
viral component into a cell by endocytosis, or fusion of a viral
component to a cell membrane.
[0092] A therapeutic molecule of this invention may be active in
preventing or inhibiting release of a viral component into the
cytoplasm of a cell.
[0093] In additional embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting internal cell
transport of an HBV nucleocapsid.
[0094] Aspects of this disclosure can provide a therapeutic
molecule, which can be active in preventing or inhibiting release
of HBV rcDNA in a cell.
[0095] In some embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting operation of
the viral polymerase.
[0096] Certain embodiments may provide a therapeutic molecule that
can be active in preventing or inhibiting development of an HBV
genomic DNA in a cell.
[0097] In further embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting production of a
viral RNA in a cell.
[0098] A therapeutic molecule of this invention may be active in
preventing or inhibiting viral replication in a cell.
[0099] In additional embodiments, a therapeutic molecule may be
active in preventing or inhibiting an HBV regulatory X-protein in a
cell.
[0100] Further aspects of this disclosure can provide a therapeutic
molecule that be active in preventing or inhibiting translation or
reverse transcription of a viral RNA in a cell.
[0101] In some embodiments, a therapeutic molecule of this
invention can be active in preventing or inhibiting maturation of a
viral nucleocapsid in a cell.
[0102] UNA Monomers
[0103] In some embodiments, linker group monomers can be unlocked
nucleomonomers (UNA monomers), which are small organic molecules
based on a propane-1,2,3-tri-yl-trisoxy structure as shown
below:
##STR00001##
where R.sup.1 and R.sup.2 are H, and R.sup.1 and R.sup.2 can be
phosphodiester linkages, Base can be a nucleobase, and R.sup.3 is a
functional group described below.
[0104] In another view, the UNA monomer main atoms can be drawn in
IUPAC notation as follows:
##STR00002##
where the direction of progress of the oligomer chain is from the
1-end to the 3-end of the propane residue.
[0105] Examples of a nucleobase include uracil, thymine, cytosine,
5-methylcytosine, adenine, guanine, inosine, and natural and
non-natural nucleobase analogues.
[0106] In general, because the UNA monomers are not nucleotides,
they can exhibit at least four forms in an oligomer. First, a UNA
monomer can be an internal monomer in an oligomer, where the UNA
monomer is flanked by other monomers on both sides. In this form,
the UNA monomer can participate in base pairing when the oligomer
is a duplex, for example, and there are other monomers with
nucleobases in the duplex.
[0107] Examples of UNA monomer as internal monomers flanked at both
the propane-1-yl position and the propane-3-yl position, where
R.sup.3 is --OH, are shown below.
##STR00003##
[0108] Second, a UNA monomer can be a monomer in an overhang of an
oligomer duplex, where the UNA monomer is flanked by other monomers
on both sides. In this form, the UNA monomer does not participate
in base pairing. Because the UNA monomers are flexible organic
structures, unlike nucleotides, the overhang containing a UNA
monomer will be a flexible terminator for the oligomer.
[0109] A UNA monomer can be a terminal monomer in an overhang of an
oligomer, where the UNA monomer is attached to only one monomer at
either the propane-1-yl position or the propane-3-yl position. In
this form, the UNA monomer does not participate in base pairing.
Because the UNA monomers are flexible organic structures, unlike
nucleotides, the overhang containing a UNA monomer can be a
flexible terminator for the oligomer.
[0110] Examples of a UNA monomer as a terminal monomer attached at
the propane-3-yl position are shown below.
##STR00004##
[0111] Because a UNA monomer can be a flexible molecule, a UNA
monomer as a terminal monomer can assume widely differing
conformations. An example of an energy minimized UNA monomer
conformation as a terminal monomer attached at the propane-3-yl
position is shown below.
##STR00005##
Thus, UNA oligomers having a terminal UNA monomer are significantly
different in structure from conventional nucleic acid agents, such
as siRNAs. For example, siRNAs may require that terminal monomers
or overhangs in a duplex be stabilized. In contrast, the
conformability of a terminal UNA monomer can provide UNA oligomers
with different properties.
[0112] Among other things, the structure of the UNA monomer allows
it to be attached to naturally-occurring nucleotides. A UNA
oligomer can be a chain composed of UNA monomers, as well as
various nucleotides that may be based on naturally-occurring
nucleosides.
[0113] In some embodiments, the functional group R.sup.3 of a UNA
monomer can be --OR.sup.4, --SR.sup.4, --NR.sup.4.sub.2,
--NH(C.dbd.O)R.sup.4, morpholino, morpholin-1-yl, piperazin-1-yl,
or 4-alkanoyl-piperazin-1-yl, where R.sup.4 is the same or
different for each occurrence, and can be H, alkyl, a cholesterol,
a lipid molecule, a polyamine, an amino acid, or a polypeptide.
[0114] The UNA monomers are organic molecules. UNA monomers are not
nucleic acid monomers or nucleotides, nor are they
naturally-occurring nucleosides or modified naturally-occurring
nucleosides.
[0115] A UNA oligomer of this invention is a synthetic chain
molecule. A UNA oligomer of this invention is not a nucleic acid,
nor an oligonucleotide.
[0116] In some embodiments, as shown above, a UNA monomer can be
UNA-A (designated ), UNA-U (designated ), UNA-C(designated {hacek
over (C)}), and UNA-G (designated {hacek over (G)}).
[0117] Designations that may be used herein include mA, mG, mC, and
mU, which refer to the 2'-O-Methyl modified ribonucleotides.
[0118] Designations that may be used herein include lower case c
and u, which refer to the 2'-O-methyl modified ribonucleotides.
[0119] Designations that may be used herein include dT, which
refers to a 2'-deoxy T nucleotide.
[0120] Additional Monomers for Oligomeric Agents
[0121] As used herein, in the context of oligomer sequences, the
symbol X represents a UNA monomer.
[0122] As used herein, in the context of oligomer sequences, the
symbol N represents any natural nucleotide monomer, or a modified
nucleotide monomer.
[0123] As used herein, in the context of oligomer sequences, the
symbol Q represents a non-natural, modified, or chemically-modified
nucleotide monomer. When a Q monomer appears in one strand of the
oligomer, and is unpaired with the other strand, the monomer can
have any base attached. When a Q monomer appears in one strand of
the oligomer, and is paired with a monomer in the other strand, the
Q monomer can have any base attached that would be complementary to
the monomer in the corresponding paired position in the other
strand.
[0124] Examples of nucleic acid monomers include non-natural,
modified, and chemically-modified nucleotides, including any such
nucleotides known in the art.
[0125] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include any such nucleotides known in the art,
for example, 2'-O-methyl ribonucleotides, 2'-O-methyl purine
nucleotides, 2'-deoxy-2'-fluoro ribonucleotides, 2'-deoxy-2'-fluoro
pyrimidine nucleotides, 2'-deoxy ribonucleotides, 2'-deoxy purine
nucleotides, universal base nucleotides, 5-C-methyl-nucleotides,
and inverted deoxyabasic monomer residues.
[0126] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include 3'-end stabilized nucleotides,
3'-glyceryl nucleotides, 3'-inverted abasic nucleotides,
3'-inverted thymidine, and L-thymidine.
[0127] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include locked nucleic acid nucleotides,
2'-O,4'-C-methylene-(D-ribofuranosyl) nucleotides, 2'-methoxyethoxy
(MOE) nucleotides, 2'-methyl-thio-ethyl, 2'-deoxy-2'-fluoro
nucleotides, and 2'-O-methyl nucleotides.
[0128] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include 2'-amino nucleotides, 2'-O-amino
nucleotides, 2'-C-allyl nucleotides, and 2'-O-allyl
nucleotides.
[0129] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include N.sup.6-methyladenosine
nucleotides.
[0130] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include nucleotide monomers with modified bases
5-(3-amino)propyluridine, 5-(2-mercapto)ethyluridine,
5-bromouridine; 8-bromoguanosine, or 7-deazaadenosine.
[0131] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include 2'-O-aminopropyl substituted
nucleotides.
[0132] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include 2'-O-guanidinopropyl substituted
nucleotides.
[0133] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include Pseudouridines.
[0134] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include replacing the 2'--OH group of a
nucleotide with a 2'-R, a 2'-OR, a 2'-halogen, a 2'-SR, or a
2'-amino, 2'-azido, where R can be H, alkyl, fluorine-substituted
alkyl, alkenyl, or alkynyl.
[0135] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include replacing the 2'--OH group of a
nucleotide with a 2'-R or 2'-OR, where R can be CN, CF.sub.3,
alkylamino, or aralkyl.
[0136] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include nucleotides with a modified sugar such
as an F-HNA, an HNA, a CeNA, a bicyclic sugar, or an LNA.
[0137] Examples of non-natural, modified, and chemically-modified
nucleotide monomers include 2'-oxa-3'-aza-4' a-carbanucleoside
monomers, 3-hydroxymethyl-5-(1H-1,2,3-triazol)-isoxazolidine
monomers, and 5'-triazolyl-2'-oxa-3'-aza-4' a-carbanucleoside
monomers.
[0138] Some examples of modified nucleotides are given in Saenger,
Principles of Nucleic Acid Structure, Springer-Verlag, 1984.
[0139] Oligomeric Compounds Containing UNA Monomers
[0140] Aspects of this invention can provide structures and
compositions for UNA-containing oligomeric compounds. The
oligomeric agents may incorporate one or more UNA monomers.
Oligomeric molecules of this invention can be used as active agents
in formulations for gene regulating or gene silencing
therapeutics.
[0141] In some embodiments, this invention provides oligomeric
compounds having a structure that incorporates novel combinations
of UNA monomers with certain natural nucleotides, non-natural
nucleotides, modified nucleotides, or chemically-modified
nucleotides.
[0142] In further aspects, the oligomeric compounds can be
pharmacologically active molecules. UNA oligomers of this invention
can be used as active pharmaceutical ingredients for regulating
gene expression, and in RNA interference methods, as well as
antisense, RNA blocking, and micro-RNA strategies.
[0143] A UNA oligomer of this invention can have the structure of
Formula I
##STR00006##
wherein L.sup.1 is a linkage, n is from 19 to 29, and for each
occurrence L.sup.2 is a UNA linker group having the formula
--C.sup.1--C.sup.2--C.sup.3--, where R is attached to C.sup.2 and
has the formula --OCH(CH.sub.2R.sup.3)R.sup.5, where R.sup.3 is
--OR.sup.4, --SR.sup.4, --NR.sup.4.sub.2, --NH(C.dbd.O)R.sup.4,
morpholino, morpholin-1-yl, piperazin-1-yl, or
4-alkanoyl-piperazin-1-yl, where R.sup.4 is the same or different
for each occurrence and is H, alkyl, a cholesterol, a lipid
molecule, a polyamine, an amino acid, or a polypeptide, and where
R.sup.5 is a nucleobase, or L.sup.2(R) is a sugar such as a ribose
and R is a nucleobase, or L.sup.2 is a modified sugar such as a
modified ribose and R is a nucleobase. In certain embodiments, a
nucleobase can be a modified nucleobase. L.sup.1 can be a
phosphodiester linkage.
[0144] A UNA oligomer of this invention can be a short chain
molecule. A UNA oligomer can be a duplex pair. Thus, a UNA oligomer
can have a first strand of the duplex and a second strand of the
duplex, which is complementary to the first strand with respect to
the nucleobases, although up to three mismatches can occur. A UNA
oligomer duplex can have overhangs.
[0145] Some UNA oligomers are discussed in U.S. Pat. No. 8,314,227,
as well as US Patent Publication No. 20110313020 A1.
[0146] The target of a UNA oligomer can be a target nucleic acid.
In some embodiments, the target can be any mRNA of a subject. A UNA
oligomer can be active for gene silencing in RNA interference.
[0147] A UNA oligomer may comprise two strands that together
provide a duplex. The duplex may be composed of a first strand,
which may also be referred to as a passenger strand or sense
strand, and a second strand, which may also be referred to as a
guide strand or antisense strand.
[0148] In some aspects, a UNA oligomer of this invention can have
any number of phosphorothioate intermonomer linkages in any
position in any strand, or in both strands of a duplex
structure.
[0149] In some embodiments, any one or more of the intermonomer
linkages of a UNA oligomer can be a phosphodiester, a
phosphorothioate including dithioates, a chiral phosphorothioate,
and other chemically modified forms.
[0150] Examples of UNA oligomers of this invention include duplex
pairs, which are in general complementary. Thus, for example, SEQ
ID NO:1 can represent a first strand of a duplex and SEQ ID NO:2
can represent a second strand of the duplex, which is complementary
to the first strand.
[0151] For example, the symbol "N" in the first strand can
represent any nucleotide that is complementary to the monomer in
the corresponding position in the second strand. Example UNA
oligomers of this disclosure are shown with 2-monomer length
overhangs, although overhangs of from 1 to 8 monomers, or longer,
can be used.
[0152] The symbol "X" in a strand or oligomer represents a UNA
monomer. When a UNA monomer appears in one strand of the oligomer,
and is unpaired with the other strand, the monomer can have any
base attached. When a UNA monomer appears in one strand of the
oligomer, and is paired with a monomer in the other strand, the UNA
monomer can have any base attached that would be complementary to
the monomer in the corresponding paired position in the other
strand.
[0153] Further, when the oligomer terminates in a UNA monomer, the
terminal position has a 1-end, according to the positional
numbering shown above, instead of a 5'-end as for a nucleotide, or
the terminal position has a 3-end, according to the positional
numbering shown above, instead of a 3'-end as for a nucleotide. For
example, the UNA oligomer
TABLE-US-00001 SEQ ID NO: 1 1-XNNNNNNNNN-NNNNNNNNNN-XX-3 SEQ ID NO:
2 3-XXNNNNNNNNN-NNXXXXXXXN-5'
has a UNA monomer 1-end on the first strand, a UNA monomer 3-end on
the first strand, a UNA monomer 3-end on the second strand, and a
nucleotide 5'-end on the second strand.
[0154] Complementarity of strands can involve mismatches. In
certain embodiments, complementarity of strands can include one to
three, or more, mismatches.
[0155] In some embodiments, a UNA oligomer of this invention can
have one or more UNA monomers at the 1-end of the first strand, and
one or more UNA monomers at the 3-end of the first strand.
[0156] In further embodiments, a UNA oligomer of this invention can
have one or more UNA monomers at the 3-end of the second
strand.
[0157] In certain embodiments, a duplex UNA oligomer of this
invention can have one or more UNA monomers at the 1-end of the
first strand, one or more UNA monomers at the 3-end of the first
strand, and one or more UNA monomers at the 3-end of the second
strand.
[0158] A UNA oligomer of this invention the oligomer may have a
first strand and a second strand, each of the strands independently
being 19-23 monomers in length.
[0159] In certain embodiments, a UNA oligomer of this invention may
have a first strand that is 19-23 monomers in length.
[0160] In certain embodiments, a UNA oligomer of this invention may
have a duplex region that is 19-21 monomers in length.
[0161] In further embodiments, a UNA oligomer of this invention may
have a second strand that is 19-23 monomers in length.
[0162] In certain embodiments, a UNA oligomer of this invention may
have a first strand that is 19 monomers in length, and a second
strand that is 21 monomers in length.
[0163] In certain embodiments, a UNA oligomer of this invention may
have a first strand that is 20 monomers in length, and a second
strand that is 21 monomers in length.
[0164] In certain embodiments, a UNA oligomer of this invention may
have a first strand that is 21 monomers in length, and a second
strand that is 21 monomers in length.
[0165] In certain embodiments, a UNA oligomer of this invention may
have a first strand that is 22 monomers in length, and a second
strand that is 21 monomers in length.
[0166] A UNA oligomer of this invention for inhibiting gene
expression can have a first strand and a second strand, each of the
strands being 19-29 monomers in length. The monomers can be UNA
monomers and nucleic acid nucleoside monomers. The oligomer can
have a duplex structure of from 14 to 29 monomers in length. The
UNA oligomer can be targeted to a target gene and can exhibit
reduced off-target effects as compared to a conventional siRNA. In
some embodiments, a UNA oligomer of this invention can have a first
strand and a second strand, each of the strands being 19-23
monomers in length.
[0167] In another aspect, the UNA oligomer may have a blunt end, or
may have one or more overhangs. In some embodiments, the first and
second strands may be connected with a connecting oligomer in
between the strands, and form a duplex region with a connecting
loop at one end.
[0168] In certain embodiments, an overhang can be one or two
monomers in length.
[0169] Examples of an overhang can contain one or more UNA
monomers, natural nucleotides, non-natural nucleotides, modified
nucleotides, or chemically-modified nucleotides, and combinations
thereof.
[0170] Examples of an overhang can contain one or more
deoxythymidine nucleotides, 2'-O-methyl nucleotides, inverted
abasic monomers, inverted thymidine monomers, L-thymidine monomers,
or glyceryl nucleotides.
[0171] A UNA oligomer can mediate cleavage of a target nucleic acid
in a cell. In some processes, the second strand of the UNA
oligomer, at least a portion of which can be complementary to the
target nucleic acid, can act as a guide strand that can hybridize
to the target nucleic acid.
[0172] The second strand can be incorporated into an RNA Induced
Silencing Complex (RISC).
[0173] A UNA oligomer of this disclosure may comprise
naturally-occurring nucleic acid nucleotides, and modifications
thereof that are compatible with gene silencing activity.
[0174] In some aspects, a UNA oligomer is a double stranded
construct molecule that is able to inhibit gene expression.
[0175] As used herein, the term strand refers to a single,
contiguous chain of monomers, the chain having any number of
internal monomers and two end monomers, where each end monomer is
attached to one internal monomer on one side, and is not attached
to a monomer on the other side, so that it ends the chain.
[0176] The monomers of a UNA oligomer may be attached via
phosphodiester linkages, phosphorothioate linkages, gapped
linkages, and other variations.
[0177] In some embodiments, a UNA oligomer can include mismatches
in complementarity between the first and second strands. In other
embodiments, a UNA oligomer may have 1, or 2, or 3 mismatches. The
mismatches may occur at any position in the duplex region.
[0178] The target of a UNA oligomer can be a target nucleic acid of
a target gene.
[0179] A UNA oligomer may have one or two overhangs outside the
duplex region. The overhangs can be an unpaired portion at the end
of the first strand or second strand. The lengths of the overhang
portions of the first and second strands can be the same or
different.
[0180] A UNA oligomer may have at least one blunt end. A blunt end
does not have an overhang portion, and the duplex region at a blunt
end terminates at the same position for both the first and second
strands.
[0181] A UNA oligomer can be RISC length, which means that it has a
duplex length of less than 25 base pairs.
[0182] In certain embodiments, a UNA oligomer can be a single
strand that folds upon itself and hybridizes to itself to form a
double stranded region having a connecting loop at the end of the
double stranded region.
[0183] Examples of UNA oligomers containing five UNA monomers, and
which contain one or more Q monomers are shown in Table 1.
TABLE-US-00002 TABLE 1 Oligomeric compounds containing five UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 3 X
QNNQNNNQQQ-NQNQNQNQNX-X 4 X-XQNQNQNNNN-NQNQNQNQNQ 5
XQNNQNQNQNQ-NQNQNQNQNX-X 6 X-XQNQNQNQNQNQNQNQNQNQ 7
X-QNNQNQNNNN-NQNQNQNQNX-X 8 X-XQNQNQNQNN-NQNQNQNQNQ 9
XQNNQNQNNNN-NQNQNQNQNX-X 10 X-XQNQNQNNNN-NNNQNQNQNQ 11
XQNNQNQNNNN-NNNQNQNQNX-X 12 X-XQNQNQNNNN-NNNNNQNQNQ 13
XQNNQNQNNNN-NNNNNQNQNX-X 14 X-XQNQNQNNNN-NNNNNQNQNQ 15
XQNNQNQNNNN-NNNNNQNQNX-X 16 X-XQNQNQNNNN-NNNNNNNQNQ 17
XQNNQNNNNNN-NNNNNQNQNX-X 18 X-XQNQNQNNNN-NNNNNNNQNQ 19 X
QNNQNNNNNN-NNNNNQNQNX-X 20 X-XQNQNNNNNN-NNNNNNNQNQ 21
XQNNNNNNNNN-NNNNNQNQNX-X 22 X-XQNQNNNNNN-NNNNNNNQNQ 23 X
QNNNNNNNNN-NNNNNNNQNX-X 24 X-XQNQNNNNNN-NNNNNNNQNQ 25
X-QNNNNNNNNN-NNNNNNNQNX-X 26 X-XQNNNNNNNN-NNNNNNNQNQ 27
X-QNNNNNNNNN-NNNNNNNQNX-X 28 X-XQNNNNNNNN-NNNNNNNNNQ 29
XQNNNNNNNNN-NNNNNNNNNX-X 30 X-XQNNNNNNNN-NNNNNNNNNQ
[0184] Examples of UNA oligomers containing four UNA monomers and
additional Q monomers are shown in Table 2.
TABLE-US-00003 TABLE 2 Oligomeric compounds containing four UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 31 X
QNNQNQNQQQ-NQNQNQNQNX-Q 32 X-XQNQNQNNNN-NQNQNQNQNQ 33 X
QNNQNQNQNQNQNQNQNQNX-Q 34 X-XQNQNQNQNQ-NQNQNQNQNQ 35
X-QNNQNQNNNN-NQNQNQNQNX-Q 36 X-XQNQNQNQNN-NQNQNQNQNQ 37
X-QNNQNQNNNN-NQNQNQNQNX-Q 38 X-XQNQNQNNNN-NNNQNQNQNQ 39 X
QNNQNQNNNN-NNNQNQNQNX-Q 40 X-XQNQNQNNNN-NNNNNQNQNQ 41
XQNNQNQNNNN-NNNNNQNQNX-Q 42 X-XQNQNQNNNN-NNNNNQNQNQ 43 X
QNNQNQNNNN-NNNNNQNQNX-Q 44 X-XQNQNQNNNN-NNNNNNNQNQ 45 X
QNNQNNNNNN-NNNNNQNQNX-Q 46 X-XQNQNQNNNN-NNNNNNNQNQ 47 X
QNNQNNNNNN-NNNNNQNQNX-Q 48 X-XQNQNNNNNN-NNNNNNNQNQ 49 X
QNNNNNNNNN-NNNNNQNQNX-Q 50 X-XQNQNNNNNN-NNNNNNNQNQ 51 X
QNNNNNNNNN-NNNNNNNQNX-Q 52 X-XQNQNNNNNN-NNNNNNNQNQ 53
XQNNNNNNNNN-NNNNNNNQNX-Q 54 X-XQNNNNNNNN-NNNNNNNQNQ 55 X
QNNNNNNNNN-NNNNNNNQNX-Q 56 X-XQNNNNNNNN-NNNNNNNNNQ 57 X
QNNNNNNNNN-NNNNNNNNNX-Q 58 X-XQNNNNNNNN-NNNNNNNNNQ
[0185] Examples of UNA oligomers containing four UNA Monomers and
additional Q monomers are shown in Table 3.
TABLE-US-00004 TABLE 3 Oligomeric compounds containing four UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 59
XQNQNQNQQQ-NQNQNQNQNX-X 60 Q-XQNQNQNNNN-NQNQNQNQNQ 61
XQNQNQNQNQNQNQNQNQNX-X 62 Q-XQNQNQNQNQ-NQNQNQNQNQ 63
XQNQNQNNNN-NQNQNQNQNX-X 64 Q-XQNQNQNQNN-NQNQNQNQNQ 65
XQNQNQNNNN-NQNQNQNQNX-X 66 Q-XQNQNQNNNN-NNNQNQNQNQ 67
XQNQNQNNNN-NNNQNQNQNX-X 68 Q-XQNQNQNNNN-NNNNNQNQNQ 69
XQNQNQNNNN-NNNNNQNQNX-X 70 Q-XQNQNQNNNN-NNNNNQNQNQ 71
XQNQNQNNNN-NNNNNQNQNX-X 72 Q-XQNQNQNNNN-NNNNNNNQNQ 73
XQNQNNNNNN-NNNNNQNQNX-X 74 Q-XQNQNQNNNN-NNNNNNNQNQ 75
XQNQNNNNNN-NNNNNQNQNX-X 76 Q-XQNQNNNNNN-NNNNNNNQNQ 77
XQNNNNNNNN-NNNNNQNQNX-X 78 Q-XQNQNNNNNN-NNNNNNNQNQ 79
XQNNNNNNNN-NNNNNNNQNX-X 80 Q-XQNQNNNNNN-NNNNNNNQNQ 81
XQNNNNNNNN-NNNNNNNQNX-X 82 Q-XQNNNNNNNN-NNNNNNNQNQ 83
XQNNNNNNNN-NNNNNNNQNX-X 84 Q-XQNNNNNNNN-NNNNNNNNNQ 85
XQNNNNNNNN-NNNNNNNNNX-X 86 Q-XQNNNNNNNN-NNNNNNNNNQ
[0186] Examples of UNA oligomers containing three UNA monomers and
additional Q monomers are shown in Table 4.
TABLE-US-00005 TABLE 4 Oligomeric compounds containing three UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 87
XQNQNQNQQQ-NQNQNQNQNX-Q 88 Q-XQNQNQNNNN-NQNQNQNQNQ 89
XQNQNQNQNQNQNQNQNQNX-Q 90 Q-XQNQNQNQNQ-NQNQNQNQNQ 91
XQNQNQNNNN-NQNQNQNQNX-Q 92 Q-XQNQNQNQNN-NQNQNQNQNQ 93
XQNQNQNNNN-NQNQNQNQNX-Q 94 Q-XQNQNQNNNN-NNNQNQNQNQ 95
XQNQNQNNNN-NNNQNQNQNX-Q 96 Q-XQNQNQNNNN-NNNNNQNQNQ 97
XQNQNQNNNN-NNNNNQNQNX-Q 98 Q-XQNQNQNNNN-NNNNNQNQNQ 99
XQNQNQNNNN-NNNNNQNQNX-Q 100 Q-XQNQNQNNNN-NNNNNNNQNQ 101
XQNQNNNNNN-NNNNNQNQNX-Q 102 Q-XQNQNQNNNN-NNNNNNNQNQ 103
XQNQNNNNNN-NNNNNQNQNX-Q 104 Q-XQNQNNNNNN-NNNNNNNQNQ 105
XQNNNNNNNN-NNNNNQNQNX-Q 106 Q-XQNQNNNNNN-NNNNNNNQNQ 107
XQNNNNNNNN-NNNNNNNQNX-Q 108 Q-XQNQNNNNNN-NNNNNNNQNQ 109
XQNNNNNNNN-NNNNNNNQNX-Q 110 Q-XQNNNNNNNN-NNNNNNNQNQ 111
XQNNNNNNNN-NNNNNNNQNX-Q 112 Q-XQNNNNNNNN-NNNNNNNNNQ 113
XQNNNNNNNN-NNNNNNNNNX-Q 114 Q-XQNNNNNNNN-NNNNNNNNNQ
[0187] Examples of UNA oligomers containing six UNA Monomers and
additional Q monomers are shown in Table 5.
TABLE-US-00006 TABLE 5 Oligomeric compounds containing six UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 115
XQNQNQNQQQ-NQNQNQNQNX-X 116 X-XQNQNQNNNN-NQNQNQNQXQ 117
XQNQNQNQQQNQNQNQNQNX-X 118 X-XQNQNQNNNN-NQNQNQNXNQ 119
XQNQNQNQQQ-NQNQNQNQNX-X 120 X-XQNQNQNNNN-NQNQNQXQNQ 121
XQNQNQNQQQ-NQNQNQNQNX-X 122 X-XQNQNQNNNN-NQNQNXNQNQ 123
XQNQNQNQQQNQNQNQNQNX-X 124 X-XQNQNQNNNN-NQNQXQNQNQ 125
XQNQNQNQQQ-NQNQNQNQNX-X 126 X-XQNQNQNNNN-NQNXNQNQNQ 127
XQNQNQNQQQ-NQNQNQNQNX-X 128 X-XQNQNQNNNN-NQXQNQNQNQ
[0188] Examples of UNA oligomers containing seven UNA monomers and
additional Q monomers are shown in Table 6.
TABLE-US-00007 TABLE 6 Oligomeric compounds containing seven UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 129
XQNQNQNQQQ-NQNQNQNQNX-X 130 X-XQNQNQNNNN-NQNQNQNXXQ 131
XQNQNQNQQQ-NQNQNQNQNX-X 132 X-XQNQNQNNNN-NQNQNQXQXQ 133
XQNQNQNQQQ-NQNQNQNQNX-X 134 X-XQNQNQNNNN-NQNQNXNQXQ 135
XQNQNQNQQQ-NQNQNQNQNX-X 136 X-XQNQNQNNNN-NQNQXQNXNQ 137
XQNQNQNQQQ-NQNQNQNQNX-X 138 X-XQNQNQNNNN-NQNQNXXQNQ 139
XQNQNQNQQQNQNQNQNQNX-X 140 X-XQNQNQNNNN-NQNXNQXQNQ 141
XQNQNQNQQQ-NQNQNQNQNX-X 142 X-XQNQNQNNNN-NQNQXXNQNQ
[0189] Examples of UNA oligomers containing five UNA monomers and
additional Q monomers are shown in Table 7.
TABLE-US-00008 TABLE 7 Oligomeric compounds containing five UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 143
XQNQNQNQQQ-NQNQNQNQNX-Q 144 X-XQNQNQNNNN-NQNQNQNQXQ 145
XQNQNQNQQQ-NQNQNQNQNX-Q 146 X-XQNQNQNNNN-NQNQNQNXNQ 147
XQNQNQNQQQ-NQNQNQNQNX-Q 148 X-XQNQNQNNNN-NQNQNQXQNQ 149
XQNQNQNQQQ-NQNQNQNQNX-Q 150 X-XQNQNQNNNN-NQNQNXNQNQ 151
XQNQNQNQQQ-NQNQNQNQNX-Q 152 X-XQNQNQNNNN-NQNQXQNQNQ 153
XQNQNQNQQQNQNQNQNQNX-Q 154 X-XQNQNQNNNN-NQNXNQNQNQ 155
XQNQNQNQQQ-NQNQNQNQNX-Q 156 X-XQNQNQNNNN-NQXQNQNQNQ
[0190] Examples of UNA oligomers containing six UNA monomers and
additional Q monomers are shown in Table 8.
TABLE-US-00009 TABLE 8 Oligomeric compounds containing six UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 157
XQNQNQNQQQ-NQNQNQNQNX-Q 158 X-XQNQNQNNNN-NQNQNQNXXQ 159
XQNQNQNQQQ-NQNQNQNQNX-Q 160 X-XQNQNQNNNN-NQNQNQXQXQ 161
XQNQNQNQQQ-NQNQNQNQNX-Q 162 X-XQNQNQNNNN-NQNQNXNQXQ 163
XQNQNQNQQQ-NQNQNQNQNX-Q 164 X-XQNQNQNNNN-NQNQXQNXNQ 165
XQNQNQNQQQ-NQNQNQNQNX-Q 166 X-XQNQNQNNNN-NQNQNXXQNQ 167
XQNQNQNQQQNQNQNQNQNX-Q 168 X-XQNQNQNNNN-NQNXNQXQNQ 169
XQNQNQNQQQ-NQNQNQNQNX-Q 170 X-XQNQNQNNNN-NQNQXXNQNQ
[0191] Examples of UNA oligomers containing five UNA monomers and
additional Q monomers are shown in Table 9.
TABLE-US-00010 TABLE 9 Oligomeric compounds containing five UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 171
XQNQNQNQQQ-NQNQNQNQNX-X 172 Q-XQNQNQNNNN-NQNQNQNQXQ 173
XQNQNQNQQQ-NQNQNQNQNX-X 174 Q-XQNQNQNNNN-NQNQNQNXNQ 175
XQNQNQNQQQ-NQNQNQNQNX-X 176 Q-XQNQNQNNNN-NQNQNQXQNQ 177
XQNQNQNQQQ-NQNQNQNQNX-X 178 Q-XQ NQNQNNNN-NQNQNXNQNQ 179
XQNQNQNQQQ-NQNQNQNQNX-X 180 Q-XQNQNQNNNN-NQNQXQNQNQ 181
XQNQNQNQQQNQNQNQNQNX-X 182 Q-XQNQNQNNNN-NQNXNQNQNQ 183
XQNQNQNQQQ-NQNQNQNQNX-X 184 Q-XQNQNQNNNN-NQXQNQNQNQ
[0192] Examples of UNA oligomers containing six UNA monomers and
additional Q monomers are shown in Table 10.
TABLE-US-00011 TABLE 10 Oligomeric compounds containing six UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 185
XQNQNQNQQQ-NQNQNQNQNX-X 186 Q-XQNQNQNNNN-NQNQNQNXXQ 187
XQNQNQNQQQNQNQNQNQNX-X 188 Q-XQNQNQNNNN-NQNQNQXQXQ 189
XQNQNQNQQQ-NQNQNQNQNX-X 190 Q-XQNQNQNNNN-NQNQNXNQXQ 191
XQNQNQNQQQ-NQNQNQNQNX-X 192 Q-XQNQNQNNNN-NQNQXQNXNQ 193
XQNQNQNQQQNQNQNQNQNX-X 194 Q-XQNQNQNNNN-NQNQNXXQNQ 195
XQNQNQNQQQ-NQNQNQNQNX-X 196 Q-XQNQNQNNNN-NQNXNQXQNQ 197
XQNQNQNQQQ-NQNQNQNQNX-X 198 Q-XQNQNQNNNN-NQNQXXNQNQ
[0193] Examples of UNA oligomers containing four UNA monomers and
additional Q monomers are shown in Table 11.
TABLE-US-00012 TABLE 11 Oligomeric compounds containing four UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 199
XQNQNQNQQQ-NQNQNQNQNX-Q 200 Q-XQNQNQNNNN-NQNQNQNQXQ 201
XQNQNQNQQQ-NQNQNQNQNX-Q 202 Q-XQNQNQNNNN-NQNQNQNXNQ 203
XQNQNQNQQQ-NQNQNQNQNX-Q 204 Q-XQNQNQNNNN-NQNQNQXQNQ 205
XQNQNQNQQQ-NQNQNQNQNX-Q 206 Q-XQNQNQNNNN-NQNQNXNQNQ 207
XQNQNQNQQQ-NQNQNQNQNX-Q 208 Q-XQNQNQNNNN-NQNQXQNQNQ 209
XQNQNQNQQQNQNQNQNQNX-Q 210 Q-XQNQNQNNNN-NQNXNQNQNQ 211
XQNQNQNQQQ-NQNQNQNQNX-Q 212 Q-XQNQNQNNNN-NQXQNQNQNQ
[0194] Examples of UNA oligomers containing five UNA monomers and
additional Q monomers are shown in Table 12.
TABLE-US-00013 TABLE 12 Oligomeric compounds containing five UNA
monomers and additional Q monomers SEQ ID NO: OLIGOMER 213
XQNQNQNQQQ-NQNQNQNQNX-Q 214 Q-XQNQNQNNNN-NQNQNQNXXQ 215
XQNQNQNQQQ-NQNQNQNQNX-Q 216 Q-XQNQNQNNNN-NQNQNQXQXQ 217
XQNQNQNQQQ-NQNQNQNQNX-Q 218 Q-XQNQNQNNNN-NQNQNXNQXQ 219
XQNQNQNQQQ-NQNQNQNQNX-Q 220 Q-XQNQNQNNNN-NQNQXQNXNQ 221
XQNQNQNQQQ-NQNQNQNQNX-Q 222 Q-XQNQNQNNNN-NQNQNXXQNQ 223
XQNQNQNQQQNQNQNQNQNX-Q 224 Q-XQNQNQNNNN-NQNXNQXQNQ 225
XQNQNQNQQQ-NQNQNQNQNX-Q 226 Q-XQNQNQNNNN-NQNQXXNQNQ
[0195] Examples of UNA oligomers containing seven or more UNA
monomers and additional Q monomers are shown in Table 13.
TABLE-US-00014 TABLE 13 Oligomeric compounds containing seven or
more UNA monomers and additional Q monomers SEQ ID NO: OLIGOMER 227
XQNQNQNQQQ-NQNQNQNQNX-X 228 X-XQNQNQNNNN-NQNQXQXQXQ 229
XQNQNQNQQQ-NQNQNQNQNX-Q 230 X-XQNQNQNNNN-NQNQNQXXXQ 231
XQNQNQNQQQ-NQNQNQNQNX-X 232 Q-XQNQNQNNNN-NQNXXXNQNQ 233
XQNQNQNQQQ-NQNQNQNQNX-Q 234 Q-XQNQNQNNNN-NQNXXXXXXQ 235
XQNQNQNQQQ-NQNQNQNQNX-X 236 X-XQNQNQNNNN-NQNXXXXXXQ
[0196] An oligomeric compound of this invention may have any one of
the structures shown in Tables 1 to 13.
[0197] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer.
[0198] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is less than twenty.
[0199] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is less than twelve.
[0200] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is less than ten.
[0201] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is less than eight.
[0202] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is from 1 to 20.
[0203] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is from 1 to 15.
[0204] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a Q monomer, and where the
number of Q monomers is from 1 to 9.
[0205] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide.
[0206] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is less than twenty.
[0207] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is less than twelve.
[0208] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is less than ten.
[0209] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is less than eight.
[0210] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is from 1 to 20.
[0211] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is from 1 to 15.
[0212] In some embodiments, an oligomeric compound of this
invention may have a first strand and a second strand, each of the
strands independently being 19-23 monomers in length, where any
monomer that is not a UNA monomer can be a 2'-O-Methyl modified
ribonucleotide, and where the number of 2'-O-Methyl modified
ribonucleotides is from 1 to 9.
[0213] In further aspects, an oligomeric compound of this invention
may have a first strand and a second strand, each of the strands
independently being 19-23 monomers in length, where any monomer
that is not a UNA monomer can be a Q monomer, and where the
oligomeric compound does not contain fluorine.
[0214] Embodiments of this invention advantageously provide
oligomeric compounds, which are active agents against HBV and do
not contain fluorine.
[0215] Methods of this invention include the treatment and/or
prevention of HBV disease in a subject. A subject can be a
mammalian subject, including a human subject.
HBV Component Target Sequences
[0216] As used herein, "Ref Pos" refers to reference position,
which is the numerical position of a reference nucleotide in an HBV
genome. The reference position is the position that corresponds
target-wise to the 5' end of the sense strand of the oligomeric
compound of this invention. The reference positions are numerical
nucleotide positions based on a reference genome, which as used
herein is HBV Genotype A2, Accession No. HE974376. Thus, a
reference position number by itself refers to one sequence from the
reference genome, and each sequence can be used in an oligomeric
compound of this invention. Table 14 shows genomic positions for
the HBV reference genome.
TABLE-US-00015 TABLE 14 HBV genomic positions Start End Gene 1 835
S 1 1623 Pol 1374 1838 X 1901 2458 C 2307 3221 Pol 2854 3221 S
[0217] In FIG. 1 is shown a map of HBV protein coding regions and
selected transcripts for the reference genome HE974376. Nucleotide
position 1/3221 is designated at the top. Further designations are
as follows: pre-S1, large HBsAg; pre-S2, medium HBsAg; S, HBsAg; P,
polymerase; X, HBx protein; pre-C, pre-core/HBeAg; C, HB core Ag.
The 2.4 kb, 2.1 kb, and 0.7 kb transcripts coding for the
pre-S1/pre-S2/S, as well as the transcript coding the X protein are
shown. The pre-Core/HBeAg protein is generated from a long, 3.5 kb
transcript (not shown) originating at position .about.1700, while
the core and polymerase proteins and the pre-genomic RNA used as a
template for viral replication are generated from a .about.200 nt
shorter transcript.
[0218] The ranges of reference positions for certain UNA oligomers,
designated UNA oligomer 1, UNA oligomer 2, and UNA oligomer 3, are
shown in FIG. 1.
[0219] In some aspects, the inventive oligomers of this disclosure
may target the long transcript coding for HBV core and polymerase
proteins.
[0220] UNA Oligomers Targeting HBV
[0221] Examples of base sequences of this invention targeted to an
HBV component are shown in Table 15.
[0222] An oligomeric compound of this invention can be formed
having a first strand and a second strand each being 21 monomers in
length. The first strand can have 19 contiguous monomers with a
sequence of attached bases shown in Table 15 (sense), and two
additional overhang monomers on the 3' end. The second strand can
have 19 contiguous monomers with a sequence of attached bases shown
in Table 15 (antisense), and two additional overhang monomers on
the 3' end. The overhang monomers can be any of NN, QQ, XX, NX, NQ,
XN, XQ, QN, and QX. For example, XQ can be UNA-U/mU, or
UNA-U/*/dT.
[0223] An oligomeric compound of this invention can be composed of
monomers. The monomers can have attached bases. An oligomeric
compound of this invention can have a sequence of attached bases.
The sequences of bases shown in Table 15 do not indicate to which
monomer each of the bases in the sequence is attached. Thus, each
sequence shown in Table 15 refers to a large number of small
molecules, each of which is composed of UNA monomers, as well as
nucleic acid monomers.
[0224] In some aspects, an oligomeric compound of this invention
can be described by a sequence of attached bases, for example as
shown in Table 15, and being substituted forms thereof. As used
herein, substituted forms include differently substituted UNA
monomers, as well as differently substituted or modified nucleic
acid monomers, as are further described herein.
[0225] In some embodiments, one or more of three monomers at each
end of each strand can be connected by a phosphorothioate, a chiral
phosphorothioate, or a phosphorodithioate linkage.
[0226] For example, a compound may have one phosphorothioate
linkage between two monomers at the 5' end of the first strand, one
phosphorothioate linkage between two monomers at the 3' end of the
first strand, one phosphorothioate linkage between monomers at the
second and third positions from the 3' end of the first strand, and
one phosphorothioate linkage between two monomers at the 3' end of
the second strand.
[0227] In certain embodiments, a compound may have two or three
phosphorothioate linkages at the 5' end of the first strand, two or
three phosphorothioate linkages at the 3' end of the first strand,
and one phosphorothioate linkage at the 3' end of the second
strand.
[0228] In additional embodiments, a compound may have one to three
phosphorothioate linkages at the 5' end of the first strand, two or
three phosphorothioate linkages at the 3' end of the first strand,
two phosphorothioate linkages at the 5' end of the second strand,
and two phosphorothioate linkages at the 3' end of the second
strand.
[0229] In some examples, a compound may have a deoxythymidine
nucleotide at the 3' end of the first strand, at the 3' end of the
second strand, or at both the 3' end of the first strand and the 3'
end of the second strand.
[0230] In some aspects, a compound may contain one to five UNA
monomers.
[0231] In certain aspects, a compound may contain three UNA
monomers.
[0232] In some embodiments, a compound may contain a UNA monomer at
the 1-end of the first strand (5' end), a UNA monomer at the 3-end
of the first strand (3' end), and a UNA monomer at the second
position from the 3' end of the second strand.
[0233] In certain embodiments, a compound may contain a UNA monomer
at any one or more of positions 2 to 8 from the 5' end of the
second strand (seed region).
TABLE-US-00016 TABLE 15 HBV sense and antisense sequences SEQ REF
SEQ Sense (5'-3') ID Antisense (5'-3') POS ID NO SEQ ID NOS: 237 to
548 NO SEQ ID NOS: 549 to 860 1525 237 CGCACCUCUCUUUACGCGG 549
CCGCGUAAAGAGAGGUGCG 251 238 GACUCGUGGUGGACUUCUC 550
GAGAAGUCCACCACGAGUC 254 239 UCGUGGUGGACUUCUCUCA 551
UGAGAGAAGUCCACCACGA 374 240 UGGAUGUGUCUGCGGCGUU 552
AACGCCGCAGACACAUCCA 1575 241 CCGUGUGCACUUCGCUUCA 553
UGAAGCGAAGUGCACACGG 1577 242 GUGUGCACUUCGCUUCACC 554
GGUGAAGCGAAGUGCACAC 1578 243 UGUGCACUUCGCUUCACCU 555
AGGUGAAGCGAAGUGCACA 1579 244 GUGCACUUCGCUUCACCUC 556
GAGGUGAAGCGAAGUGCAC 1581 245 GCACUUCGCUUCACCUCUG 557
CAGAGGUGAAGCGAAGUGC 1863 246 UUCAAGCCUCCAAGCUGUG 558
CACAGCUUGGAGGCUUGAA 1864 247 UCAAGCCUCCAAGCUGUGC 559
GCACAGCUUGGAGGCUUGA 1865 248 CAAGCCUCCAAGCUGUGCC 560
GGCACAGCUUGGAGGCUUG 1866 249 AAGCCUCCAAGCUGUGCCU 561
AGGCACAGCUUGGAGGCUU 247 250 UCUAGACUCGUGGUGGACU 562
AGUCCACCACGAGUCUAGA 248 251 CUAGACUCGUGGUGGACUU 563
AAGUCCACCACGAGUCUAG 249 252 UAGACUCGUGGUGGACUUC 564
GAAGUCCACCACGAGUCUA 250 253 AGACUCGUGGUGGACUUCU 565
AGAAGUCCACCACGAGUCU 376 254 GAUGUGUCUGCGGCGUUUU 566
AAAACGCCGCAGACACAUC 378 255 UGUGUCUGCGGCGUUUUAU 567
AUAAAACGCCGCAGACACA 380 256 UGUCUGCGGCGUUUUAUCA 568
UGAUAAAACGCCGCAGACA 1776 257 GGAGGCUGUAGGCAUAAAU 569
AUUUAUGCCUACAGCCUCC 1777 258 GAGGCUGUAGGCAUAAAUU 570
AAUUUAUGCCUACAGCCUC 1779 259 GGCUGUAGGCAUAAAUUGG 571
CCAAUUUAUGCCUACAGCC 1780 260 GCUGUAGGCAUAAAUUGGU 572
ACCAAUUUAUGCCUACAGC 1818 261 AACUUUUUCACCUCUGCCU 573
AGGCAGAGGUGAAAAAGUU 244 262 GAGUCUAGACUCGUGGUGG 574
CCACCACGAGUCUAGACUC 245 263 AGUCUAGACUCGUGGUGGA 575
UCCACCACGAGUCUAGACU 246 264 GUCUAGACUCGUGGUGGAC 576
GUCCACCACGAGUCUAGAC 409 265 CAUCCUGCUGCUAUGCCUC 577
GAGGCAUAGCAGCAGGAUG 411 266 UCCUGCUGCUAUGCCUCAU 578
AUGAGGCAUAGCAGCAGGA 412 267 CCUGCUGCUAUGCCUCAUC 579
GAUGAGGCAUAGCAGCAGG 413 268 CUGCUGCUAUGCCUCAUCU 580
AGAUGAGGCAUAGCAGCAG 414 269 UGCUGCUAUGCCUCAUCUU 581
AAGAUGAGGCAUAGCAGCA 1781 270 CUGUAGGCAUAAAUUGGUC 582
GACCAAUUUAUGCCUACAG 1782 271 UGUAGGCAUAAAUUGGUCU 583
AGACCAAUUUAUGCCUACA 252 272 ACUCGUGGUGGACUUCUCU 584
AGAGAAGUCCACCACGAGU 253 273 CUCGUGGUGGACUUCUCUC 585
GAGAGAAGUCCACCACGAG 1576 274 CGUGUGCACUUCGCUUCAC 586
GUGAAGCGAAGUGCACACG 1580 275 UGCACUUCGCUUCACCUCU 587
AGAGGUGAAGCGAAGUGCA 1582 276 CACUUCGCUUCACCUCUGC 588
GCAGAGGUGAAGCGAAGUG 1583 277 ACUUCGCUUCACCUCUGCA 589
UGCAGAGGUGAAGCGAAGU 1867 278 AGCCUCCAAGCUGUGCCUU 590
AAGGCACAGCUUGGAGGCU 1868 279 GCCUCCAAGCUGUGCCUUG 591
CAAGGCACAGCUUGGAGGC 2382 280 GAACUCCCUCGCCUCGCAG 592
CUGCGAGGCGAGGGAGUUC 2383 281 AACUCCCUCGCCUCGCAGA 593
UCUGCGAGGCGAGGGAGUU 2384 282 ACUCCCUCGCCUCGCAGAC 594
GUCUGCGAGGCGAGGGAGU 2385 283 CUCCCUCGCCUCGCAGACG 595
CGUCUGCGAGGCGAGGGAG 56 284 CCUGCUGGUGGCUCCAGUU 596
AACUGGAGCCACCAGCAGG 57 285 CUGCUGGUGGCUCCAGUUC 597
GAACUGGAGCCACCAGCAG 375 286 GGAUGUGUCUGCGGCGUUU 598
AAACGCCGCAGACACAUCC 377 287 AUGUGUCUGCGGCGUUUUA 599
UAAAACGCCGCAGACACAU 379 288 GUGUCUGCGGCGUUUUAUC 600
GAUAAAACGCCGCAGACAC 381 289 GUCUGCGGCGUUUUAUCAU 601
AUGAUAAAACGCCGCAGAC 637 290 CCUAUGGGAGUGGGCCUCA 602
UGAGGCCCACUCCCAUAGG 638 291 CUAUGGGAGUGGGCCUCAG 603
CUGAGGCCCACUCCCAUAG 1584 292 CUUCGCUUCACCUCUGCAC 604
GUGCAGAGGUGAAGCGAAG 1585 293 UUCGCUUCACCUCUGCACG 605
CGUGCAGAGGUGAAGCGAA 1586 294 UCGCUUCACCUCUGCACGU 606
ACGUGCAGAGGUGAAGCGA 1778 295 AGGCUGUAGGCAUAAAUUG 607
CAAUUUAUGCCUACAGCCU 1819 296 ACUUUUUCACCUCUGCCUA 608
UAGGCAGAGGUGAAAAAGU 410 297 AUCCUGCUGCUAUGCCUCA 609
UGAGGCAUAGCAGCAGGAU 415 298 GCUGCUAUGCCUCAUCUUC 610
GAAGAUGAGGCAUAGCAGC 416 299 CUGCUAUGCCUCAUCUUCU 611
AGAAGAUGAGGCAUAGCAG 417 300 UGCUAUGCCUCAUCUUCUU 612
AAGAAGAUGAGGCAUAGCA 1783 301 GUAGGCAUAAAUUGGUCUG 613
CAGACCAAUUUAUGCCUAC 1869 302 CCUCCAAGCUGUGCCUUGG 614
CCAAGGCACAGCUUGGAGG 255 303 CGUGGUGGACUUCUCUCAA 615
UUGAGAGAAGUCCACCACG 256 304 GUGGUGGACUUCUCUCAAU 616
AUUGAGAGAAGUCCACCAC 257 305 UGGUGGACUUCUCUCAAUU 617
AAUUGAGAGAAGUCCACCA 258 306 GGUGGACUUCUCUCAAUUU 618
AAAUUGAGAGAAGUCCACC 259 307 GUGGACUUCUCUCAAUUUU 619
AAAAUUGAGAGAAGUCCAC 260 308 UGGACUUCUCUCAAUUUUC 620
GAAAAUUGAGAGAAGUCCA 262 309 GACUUCUCUCAAUUUUCUA 621
UAGAAAAUUGAGAGAAGUC 263 310 ACUUCUCUCAAUUUUCUAG 622
CUAGAAAAUUGAGAGAAGU 264 311 CUUCUCUCAAUUUUCUAGG 623
CCUAGAAAAUUGAGAGAAG 265 312 UUCUCUCAAUUUUCUAGGG 624
ccCUAGAAAAUUGAGAGAA 266 313 UCUCUCAAUUUUCUAGGGG 625
ccCCUAGAAAAUUGAGAGA 1264 314 AUCCAUACUGCGGAACUCC 626
GGAGUUCCGCAGUAUGGAU 1265 315 UCCAUACUGCGGAACUCCU 627
AGGAGUUCCGCAGUAUGGA 2376 316 GAAGAAGAACUCCCUCGCC 628
GGCGAGGGAGUUCUUCUUC 2377 317 AAGAAGAACUCCCUCGCCU 629
AGGCGAGGGAGUUCUUCUU 2378 318 AGAAGAACUCCCUCGCCUC 630
GAGGCGAGGGAGUUCUUCU 2379 319 GAAGAACUCCCUCGCCUCG 631
CGAGGCGAGGGAGUUCUUC 2380 320 AAGAACUCCCUCGCCUCGC 632
GCGAGGCGAGGGAGUUCUU 2381 321 AGAACUCCCUCGCCUCGCA 633
UGCGAGGCGAGGGAGUUCU 243 322 AGAGUCUAGACUCGUGGUG 634
CACCACGAGUCUAGACUCU 261 323 GGACUUCUCUCAAUUUUCU 635
AGAAAAUUGAGAGAAGUCC 1263 324 GAUCCAUACUGCGGAACUC 636
GAGUUCCGCAGUAUGGAUC 1815 325 UGCAACUUUUUCACCUCUG 637
CAGAGGUGAAAAAGUUGCA 1816 326 GCAACUUUUUCACCUCUGC 638
GCAGAGGUGAAAAAGUUGC 1817 327 CAACUUUUUCACCUCUGCC 639
GGCAGAGGUGAAAAAGUUG 301 328 UGGCCAAAAUUCGCAGUCC 640
GGACUGCGAAUUUUGGCCA 302 329 GGCCAAAAUUCGCAGUCCC 641
GGGACUGCGAAUUUUGGCC 1261 330 CCGAUCCAUACUGCGGAAC 642
GUUCCGCAGUAUGGAUCGG 1262 331 CGAUCCAUACUGCGGAACU 643
AGUUCCGCAGUAUGGAUCG 1820 332 CUUUUUCACCUCUGCCUAA 644
UUAGGCAGAGGUGAAAAAG 1821 333 UUUUUCACCUCUGCCUAAU 645
AUUAGGCAGAGGUGAAAAA 1822 334 UUUUCACCUCUGCCUAAUC 646
GAUUAGGCAGAGGUGAAAA 1823 335 UUUCACCUCUGCCUAAUCA 647
UGAUUAGGCAGAGGUGAAA 1874 336 AAGCUGUGCCUUGGGUGGC 648
GCCACCCAAGGCACAGCUU 1875 337 AGCUGUGCCUUGGGUGGCU 649
AGCCACCCAAGGCACAGCU 1876 338 GCUGUGCCUUGGGUGGCUU 650
AAGCCACCCAAGGCACAGC 1877 339 CUGUGCCUUGGGUGGCUUU 651
AAAGCCACCCAAGGCACAG 2267 340 GGAGUGUGGAUUCGCACUC 652
GAGUGCGAAUCCACACUCC 2268 341 GAGUGUGGAUUCGCACUCC 653
GGAGUGCGAAUCCACACUC 242 342 CAGAGUCUAGACUCGUGGU 654
ACCACGAGUCUAGACUCUG 1654 343 AUAAGAGGACUCUUGGACU 655
AGUCCAAGAGUCCUCUUAU 1774 344 UAGGAGGCUGUAGGCAUAA 656
UUAUGCCUACAGCCUCCUA 1775 345 AGGAGGCUGUAGGCAUAAA 657
UUUAUGCCUACAGCCUCCU 1813 346 CAUGCAACUUUUUCACCUC 658
GAGGUGAAAAAGUUGCAUG 1814 347 AUGCAACUUUUUCACCUCU 659
AGAGGUGAAAAAGUUGCAU 1824 348 UUCACCUCUGCCUAAUCAU 660
AUGAUUAGGCAGAGGUGAA 1825 349 UCACCUCUGCCUAAUCAUC 661
GAUGAUUAGGCAGAGGUGA 1826 350 CACCUCUGCCUAAUCAUCU 662
AGAUGAUUAGGCAGAGGUG 1870 351 CUCCAAGCUGUGCCUUGGG 663
CCCAAGGCACAGCUUGGAG 1871 352 UCCAAGCUGUGCCUUGGGU 664
ACCCAAGGCACAGCUUGGA 1872 353 CCAAGCUGUGCCUUGGGUG 665
CACCCAAGGCACAGCUUGG 1873 354 CAAGCUGUGCCUUGGGUGG 666
CCACCCAAGGCACAGCUUG 2373 355 CUAGAAGAAGAACUCCCUC 667
GAGGGAGUUCUUCUUCUAG 2374 356 UAGAAGAAGAACUCCCUCG 668
CGAGGGAGUUCUUCUUCUA 2375 357 AGAAGAAGAACUCCCUCGC 669
GCGAGGGAGUUCUUCUUCU 1862 358 GUUCAAGCCUCCAAGCUGU 670
ACAGCUUGGAGGCUUGAAC
2297 359 AGACCACCAAAUGCCCCUA 671 UAGGGGCAUUUGGUGGUCU 2298 360
GACCACCAAAUGCCCCUAU 672 AUAGGGGCAUUUGGUGGUC 2299 361
ACCACCAAAUGCCCCUAUC 673 GAUAGGGGCAUUUGGUGGU 599 362
UGUAUUCCCAUCCCAUCAU 674 AUGAUGGGAUGGGAAUACA 600 363
GUAUUCCCAUCCCAUCAUC 675 GAUGAUGGGAUGGGAAUAC 703 364
CGUAGGGCUUUCCCCCACU 676 AGUGGGGGAAAGCCCUACG 704 365
GUAGGGCUUUCCCCCACUG 677 CAGUGGGGGAAAGCCCUAC 705 366
UAGGGCUUUCCCCCACUGU 678 ACAGUGGGGGAAAGCCCUA 1259 367
UGCCGAUCCAUACUGCGGA 679 UCCGCAGUAUGGAUCGGCA 1260 368
GCCGAUCCAUACUGCGGAA 680 UUCCGCAGUAUGGAUCGGC 1518 369
CACGGGGCGCACCUCUCUU 681 AAGAGAGGUGCGCCCCGUG 1519 370
ACGGGGCGCACCUCUCUUU 682 AAAGAGAGGUGCGCCCCGU 1520 371
CGGGGCGCACCUCUCUUUA 683 UAAAGAGAGGUGCGCCCCG 1521 372
GGGGCGCACCUCUCUUUAC 684 GUAAAGAGAGGUGCGCCCC 1522 373
GGGCGCACCUCUCUUUACG 685 CGUAAAGAGAGGUGCGCCC 1523 374
GGCGCACCUCUCUUUACGC 686 GCGUAAAGAGAGGUGCGCC 1524 375
GCGCACCUCUCUUUACGCG 687 CGCGUAAAGAGAGGUGCGC 1859 376
ACUGUUCAAGCCUCCAAGC 688 GCUUGGAGGCUUGAACAGU 1860 377
CUGUUCAAGCCUCCAAGCU 689 AGCUUGGAGGCUUGAACAG 1861 378
UGUUCAAGCCUCCAAGCUG 690 CAGCUUGGAGGCUUGAACA 459 379
GUAUGUUGCCCGUUUGUCC 691 GGACAAACGGGCAACAUAC 460 380
UAUGUUGCCCGUUUGUCCU 692 AGGACAAACGGGCAACAUA 462 381
UGUUGCCCGUUUGUCCUCU 693 AGAGGACAAACGGGCAACA 1136 382
UGAACCUUUACCCCGUUGC 694 GCAACGGGGUAAAGGUUCA 1266 383
CCAUACUGCGGAACUCCUA 695 UAGGAGUUCCGCAGUAUGG 1267 384
CAUACUGCGGAACUCCUAG 696 CUAGGAGUUCCGCAGUAUG 1268 385
AUACUGCGGAACUCCUAGC 697 GCUAGGAGUUCCGCAGUAU 1517 386
CCACGGGGCGCACCUCUCU 698 AGAGAGGUGCGCCCCGUGG 2371 387
CCCUAGAAGAAGAACUCCC 699 GGGAGUUCUUCUUCUAGGG 2372 388
CCUAGAAGAAGAACUCCCU 700 AGGGAGUUCUUCUUCUAGG 2380 389
UCCCUCGCCUCGCAGACGA 701 UCGUCUGCGAGGCGAGGGA 401 390
UUCCUCUUCAUCCUGCUGC 702 GCAGCAGGAUGAAGAGGAA 402 391
UCCUCUUCAUCCUGCUGCU 703 AGCAGCAGGAUGAAGAGGA 403 392
CCUCUUCAUCCUGCUGCUA 704 UAGCAGCAGGAUGAAGAGG 404 393
CUCUUCAUCCUGCUGCUAU 705 AUAGCAGCAGGAUGAAGAG 405 394
UCUUCAUCCUGCUGCUAUG 706 CAUAGCAGCAGGAUGAAGA 406 395
CUUCAUCCUGCUGCUAUGC 707 GCAUAGCAGCAGGAUGAAG 407 396
UUCAUCCUGCUGCUAUGCC 708 GGCAUAGCAGCAGGAUGAA 408 397
UCAUCCUGCUGCUAUGCCU 709 AGGCAUAGCAGCAGGAUGA 458 398
GGUAUGUUGCCCGUUUGUC 710 GACAAACGGGCAACAUACC 461 399
AUGUUGCCCGUUUGUCCUC 711 GAGGACAAACGGGCAACAU 1426 400
UACGUCCCGUCGGCGCUGA 712 UCAGCGCCGACGGGACGUA 1427 401
ACGUCCCGUCGGCGCUGAA 713 UUCAGCGCCGACGGGACGU 1428 402
CGUCCCGUCGGCGCUGAAU 714 AUUCAGCGCCGACGGGACG 1429 403
GUCCCGUCGGCGCUGAAUC 715 GAUUCAGCGCCGACGGGAC 1430 404
UCCCGUCGGCGCUGAAUCC 716 GGAUUCAGCGCCGACGGGA 2269 405
AGUGUGGAUUCGCACUCCU 717 AGGAGUGCGAAUCCACACU 2370 406
cCCCUAGAAGAAGAACUCC 718 GGAGUUCUUCUUCUAGGGG 455 407
CAAGGUAUGUUGCCCGUUU 719 AAACGGGCAACAUACCUUG 456 408
AAGGUAUGUUGCCCGUUUG 720 CAAACGGGCAACAUACCUU 457 409
AGGUAUGUUGCCCGUUUGU 721 ACAAACGGGCAACAUACCU 1513 410
CCGACCACGGGGCGCACCU 722 AGGUGCGCCCCGUGGUCGG 1514 411
CGACCACGGGGCGCACCUC 723 GAGGUGCGCCCCGUGGUCG 1515 412
GACCACGGGGCGCACCUCU 724 AGAGGUGCGCCCCGUGGUC 1516 413
ACCACGGGGCGCACCUCUC 725 GAGAGGUGCGCCCCGUGGU 1545 414
CUCCCCGUCUGUGCCUUCU 726 AGAAGGCACAGACGGGGAG 1546 415
UCCCCGUCUGUGCCUUCUC 727 GAGAAGGCACAGACGGGGA 2417 416
CCGCGUCGCAGAAGAUCUC 728 GAGAUCUUCUGCGACGCGG 2418 417
CGCGUCGCAGAAGAUCUCA 729 UGAGAUCUUCUGCGACGCG 2419 418
GCGUCGCAGAAGAUCUCAA 730 UUGAGAUCUUCUGCGACGC 2420 419
CGUCGCAGAAGAUCUCAAU 731 AUUGAGAUCUUCUGCGACG 2421 420
GUCGCAGAAGAUCUCAAUC 732 GAUUGAGAUCUUCUGCGAC 2422 421
UCGCAGAAGAUCUCAAUCU 733 AGAUUGAGAUCUUCUGCGA 181 422
AGGACCCCUGCUCGUGUUA 734 UAACACGAGCAGGGGUCCU 182 423
GGACCCCUGCUCGUGUUAC 735 GUAACACGAGCAGGGGUCC 183 424
GACCCCUGCUCGUGUUACA 736 UGUAACACGAGCAGGGGUC 184 425
ACCCCUGCUCGUGUUACAG 737 CUGUAACACGAGCAGGGGU 185 426
CCCCUGCUCGUGUUACAGG 738 CCUGUAACACGAGCAGGGG 368 427
UAUCGCUGGAUGUGUCUGC 739 GCAGACACAUCCAGCGAUA 369 428
AUCGCUGGAUGUGUCUGCG 740 CGCAGACACAUCCAGCGAU 370 429
UCGCUGGAUGUGUCUGCGG 741 CCGCAGACACAUCCAGCGA 371 430
CGCUGGAUGUGUCUGCGGC 742 GCCGCAGACACAUCCAGCG 372 431
GCUGGAUGUGUCUGCGGCG 743 CGCCGCAGACACAUCCAGC 373 432
CUGGAUGUGUCUGCGGCGU 744 ACGCCGCAGACACAUCCAG 463 433
GUUGCCCGUUUGUCCUCUA 745 UAGAGGACAAACGGGCAAC 686 434
CCAUUUGUUCAGUGGUUCG 746 CGAACCACUGAACAAAUGG 800 435
UUACCAAUUUUCUUUUGUC 747 GACAAAAGAAAAUUGGUAA 1102 436
CCAACUUACAAGGCCUUUC 748 GAAAGGCCUUGUAAGUUGG 1103 437
CAACUUACAAGGCCUUUCU 749 AGAAAGGCCUUGUAAGUUG 1183 438
UUUGCUGACGCAACCCCCA 750 UGGGGGUUGCGUCAGCAAA 1184 439
UUGCUGACGCAACCCCCAC 751 GUGGGGGUUGCGUCAGCAA 1185 440
UGCUGACGCAACCCCCACU 752 AGUGGGGGUUGCGUCAGCA 1186 441
GCUGACGCAACCCCCACUG 753 CAGUGGGGGUUGCGUCAGC 1187 442
CUGACGCAACCCCCACUGG 754 CCAGUGGGGGUUGCGUCAG 1553 443
CUGUGCCUUCUCAUCUGCC 755 GGCAGAUGAGAAGGCACAG 1554 444
UGUGCCUUCUCAUCUGCCG 756 CGGCAGAUGAGAAGGCACA 1555 445
GUGCCUUCUCAUCUGCCGG 757 CCGGCAGAUGAGAAGGCAC 1805 446
ACCAGCACCAUGCAACUUU 758 AAAGUUGCAUGGUGCUGGU 1806 447
CCAGCACCAUGCAACUUUU 759 AAAAGUUGCAUGGUGCUGG 1807 448
CAGCACCAUGCAACUUUUU 760 AAAAAGUUGCAUGGUGCUG 1808 449
AGCACCAUGCAACUUUUUC 761 GAAAAAGUUGCAUGGUGCU 1809 450
GCACCAUGCAACUUUUUCA 762 UGAAAAAGUUGCAUGGUGC 1810 451
CACCAUGCAACUUUUUCAC 763 GUGAAAAAGUUGCAUGGUG 1811 452
ACCAUGCAACUUUUUCACC 764 GGUGAAAAAGUUGCAUGGU 1812 453
CCAUGCAACUUUUUCACCU 765 AGGUGAAAAAGUUGCAUGG 2423 454
CGCAGAAGAUCUCAAUCUC 766 GAGAUUGAGAUCUUCUGCG 177 455
UCCUAGGACCCCUGCUCGU 767 ACGAGCAGGGGUCCUAGGA 178 456
CCUAGGACCCCUGCUCGUG 768 CACGAGCAGGGGUCCUAGG 179 457
CUAGGACCCCUGCUCGUGU 769 ACACGAGCAGGGGUCCUAG 180 458
UAGGACCCCUGCUCGUGUU 770 AACACGAGCAGGGGUCCUA 186 459
CCCUGCUCGUGUUACAGGC 771 GCCUGUAACACGAGCAGGG 187 460
CCUGCUCGUGUUACAGGCG 772 CGCCUGUAACACGAGCAGG 188 461
CUGCUCGUGUUACAGGCGG 773 CCGCCUGUAACACGAGCAG 685 462
GCCAUUUGUUCAGUGGUUC 774 GAACCACUGAACAAAUGGC 1099 463
UCGCCAACUUACAAGGCCU 775 AGGCCUUGUAAGUUGGCGA 1100 464
CGCCAACUUACAAGGCCUU 776 AAGGCCUUGUAAGUUGGCG 1101 465
GCCAACUUACAAGGCCUUU 777 AAAGGCCUUGUAAGUUGGC 1230 466
GCGCAUGCGUGGAACCUUU 778 AAAGGUUCCACGCAUGCGC 1258 467
CUGCCGAUCCAUACUGCGG 779 CCGCAGUAUGGAUCGGCAG 1606 468
GCAUGGAGACCACCGUGAA 780 UUCACGGUGGUCUCCAUGC 1607 469
CAUGGAGACCACCGUGAAC 781 GUUCACGGUGGUCUCCAUG 1608 470
AUGGAGACCACCGUGAACG 782 CGUUCACGGUGGUCUCCAU 1609 471
UGGAGACCACCGUGAACGC 783 GCGUUCACGGUGGUCUCCA 1610 472
GGAGACCACCGUGAACGCC 784 GGCGUUCACGGUGGUCUCC 1611 473
GAGACCACCGUGAACGCCC 785 GGGCGUUCACGGUGGUCUC 1804 474
CACCAGCACCAUGCAACUU 786 AAGUUGCAUGGUGCUGGUG 2381 475
CCCUCGCCUCGCAGACGAA 787 UUCGUCUGCGAGGCGAGGG 3077 476
UGGGGUGGAGCCCUCAGGC 788 GCCUGAGGGCUCCACCCCA 303 477
GCCAAAAUUCGCAGUCCCC 789 GGGGACUGCGAAUUUUGGC 304 478
CCAAAAUUCGCAGUCCCCA 790 UGGGGACUGCGAAUUUUGG 305 479
CAAAAUUCGCAGUCCCCAA 791 UUGGGGACUGCGAAUUUUG 801 480
UACCAAUUUUCUUUUGUCU 792 AGACAAAAGAAAAUUGGUA 1174 481
UGCCAAGUGUUUGCUGACG 793 CGUCAGCAAACACUUGGCA 1175 482
GCCAAGUGUUUGCUGACGC 794 GCGUCAGCAAACACUUGGC 1176 483
CCAAGUGUUUGCUGACGCA 795 UGCGUCAGCAAACACUUGG
2382 484 CCUCGCCUCGCAGACGAAG 796 CUUCGUCUGCGAGGCGAGG 2408 485
UCUCAAUCGCCGCGUCGCA 797 UGCGACGCGGCGAUUGAGA 2409 486
CUCAAUCGCCGCGUCGCAG 798 CUGCGACGCGGCGAUUGAG 2410 487
UCAAUCGCCGCGUCGCAGA 799 UCUGCGACGCGGCGAUUGA 2463 488
CCUUGGACUCAUAAGGUGG 800 CCACCUUAUGAGUCCAAGG 2464 489
CUUGGACUCAUAAGGUGGG 801 CCCACCUUAUGAGUCCAAG 55 490
UCCUGCUGGUGGCUCCAGU 802 ACUGGAGCCACCAGCAGGA 668 491
UGGCUCAGUUUACUAGUGC 803 GCACUAGUAAACUGAGCCA 701 492
UUCGUAGGGCUUUCCCCCA 804 UGGGGGAAAGCCCUACGAA 1177 493
CAAGUGUUUGCUGACGCAA 805 UUGCGUCAGCAAACACUUG 1178 494
AAGUGUUUGCUGACGCAAC 806 GUUGCGUCAGCAAACACUU 1179 495
AGUGUUUGCUGACGCAACC 807 GGUUGCGUCAGCAAACACU 1180 496
GUGUUUGCUGACGCAACCC 808 GGGUUGCGUCAGCAAACAC 1181 497
UGUUUGCUGACGCAACCCC 809 GGGGUUGCGUCAGCAAACA 1182 498
GUUUGCUGACGCAACCCCC 810 GGGGGUUGCGUCAGCAAAC 1680 499
AUGUCAACGACCGACCUUG 811 CAAGGUCGGUCGUUGACAU 1681 500
UGUCAACGACCGACCUUGA 812 UCAAGGUCGGUCGUUGACA 1682 501
GUCAACGACCGACCUUGAG 813 CUCAAGGUCGGUCGUUGAC 1683 502
UCAACGACCGACCUUGAGG 814 CCUCAAGGUCGGUCGUUGA 1684 503
CAACGACCGACCUUGAGGC 815 GCCUCAAGGUCGGUCGUUG 2411 504
CAAUCGCCGCGUCGCAGAA 816 UUCUGCGACGCGGCGAUUG 2412 505
AAUCGCCGCGUCGCAGAAG 817 CUUCUGCGACGCGGCGAUU 2413 506
AUCGCCGCGUCGCAGAAGA 818 UCUUCUGCGACGCGGCGAU 2414 507
UCGCCGCGUCGCAGAAGAU 819 AUCUUCUGCGACGCGGCGA 2415 508
CGCCGCGUCGCAGAAGAUC 820 GAUCUUCUGCGACGCGGCG 2416 509
GCCGCGUCGCAGAAGAUCU 821 AGAUCUUCUGCGACGCGGC 54 510
UUCCUGCUGGUGGCUCCAG 822 CUGGAGCCACCAGCAGGAA 700 511
GUUCGUAGGGCUUUCCCCC 823 GGGGGAAAGCCCUACGAAC 702 512
UCGUAGGGCUUUCCCCCAC 824 GUGGGGGAAAGCCCUACGA 1253 513
CUCCUCUGCCGAUCCAUAC 825 GUAUGGAUCGGCAGAGGAG 1254 514
UCCUCUGCCGAUCCAUACU 826 AGUAUGGAUCGGCAGAGGA 1255 515
CCUCUGCCGAUCCAUACUG 827 CAGUAUGGAUCGGCAGAGG 1439 516
CGCUGAAUCCCGCGGACGA 828 UCGUCCGCGGGAUUCAGCG 1547 517
CCCCGUCUGUGCCUUCUCA 829 UGAGAAGGCACAGACGGGG 1548 518
CCCGUCUGUGCCUUCUCAU 830 AUGAGAAGGCACAGACGGG 1549 519
CCGUCUGUGCCUUCUCAUC 831 GAUGAGAAGGCACAGACGG 1550 520
CGUCUGUGCCUUCUCAUCU 832 AGAUGAGAAGGCACAGACG 1653 521
CAUAAGAGGACUCUUGGAC 833 GUCCAAGAGUCCUCUUAUG 1910 522
GACCCUUAUAAAGAAUUUG 834 CAAAUUCUUUAUAAGGGUC 2270 523
GUGUGGAUUCGCACUCCUC 835 GAGGAGUGCGAAUCCACAC 2361 524
GAGGCAGGUCCCCUAGAAG 836 CUUCUAGGGGACCUGCCUC 2362 525
AGGCAGGUCCCCUAGAAGA 837 UCUUCUAGGGGACCUGCCU 316 526
GUCCCCAACCUCCAAUCAC 838 GUGAUUGGAGGUUGGGGAC 317 527
UCCCCAACCUCCAAUCACU 839 AGUGAUUGGAGGUUGGGGA 452 528
UAUCAAGGUAUGUUGCCCG 840 CGGGCAACAUACCUUGAUA 453 529
AUCAAGGUAUGUUGCCCGU 841 ACGGGCAACAUACCUUGAU 687 530
CAUUUGUUCAGUGGUUCGU 842 ACGAACCACUGAACAAAUG 689 531
UUUGUUCAGUGGUUCGUAG 843 CUACGAACCACUGAACAAA 690 532
UUGUUCAGUGGUUCGUAGG 844 CCUACGAACCACUGAACAA 691 533
UGUUCAGUGGUUCGUAGGG 845 CCCUACGAACCACUGAACA 692 534
GUUCAGUGGUUCGUAGGGC 846 GCCCUACGAACCACUGAAC 693 535
UUCAGUGGUUCGUAGGGCU 847 AGCCCUACGAACCACUGAA 694 536
UCAGUGGUUCGUAGGGCUU 848 AAGCCCUACGAACCACUGA 695 537
CAGUGGUUCGUAGGGCUUU 849 AAAGCCCUACGAACCACUG 696 538
AGUGGUUCGUAGGGCUUUC 850 GAAAGCCCUACGAACCACU 697 539
GUGGUUCGUAGGGCUUUCC 851 GGAAAGCCCUACGAACCAC 698 540
UGGUUCGUAGGGCUUUCCC 852 GGGAAAGCCCUACGAACCA 699 541
GGUUCGUAGGGCUUUCCCC 853 GGGGAAAGCCCUACGAACC 1228 542
CAGCGCAUGCGUGGAACCU 854 AGGUUCCACGCAUGCGCUG 1229 543
AGCGCAUGCGUGGAACCUU 855 AAGGUUCCACGCAUGCGCU 1231 544
CGCAUGCGUGGAACCUUUG 856 CAAAGGUUCCACGCAUGCG 1256 545
CUCUGCCGAUCCAUACUGC 857 GCAGUAUGGAUCGGCAGAG 1257 546
UCUGCCGAUCCAUACUGCG 858 CGCAGUAUGGAUCGGCAGA 1438 547
GCGCUGAAUCCCGCGGACG 859 CGUCCGCGGGAUUCAGCGC 1827 548
ACCUCUGCCUAAUCAUCUC 860 GAGAUGAUUAGGCAGAGGU
[0234] UNA Oligomers Targeting HBV
[0235] Examples of base sequences of this invention targeted to an
HBV component are shown in Table 16.
[0236] An oligomeric compound of this invention can be formed
having a first strand and a second strand each being 21 monomers in
length. The first strand can have 19 contiguous monomers with a
sequence of attached bases shown in Table 16 (sense), and two
additional overhang monomers on the 3' end. The second strand can
have 19 contiguous monomers with a sequence of attached bases shown
in Table 16 (antisense), and two additional overhang monomers on
the 3' end. The overhang monomers can be any of NN, QQ, XX, NX, NQ,
XN, XQ, QN, and QX. For example, XQ can be UNA-U/mU, or
UNA-U/*/dT.
TABLE-US-00017 TABLE 16 HBV sense and antisense sequences SEQ Sense
(5'-3') SEQ Antisense (5'-3') REF ID SEQ ID NOS: ID SEQ ID NOS: POS
NO 861 to 901 NO 902 to 942 1525 861 CGCACCUCUCUUUACGCGG 902
CCGCGUAAAGAGAGGUGCG 251 862 GACUCGUGGUGGACUUCUC 903
GAGAAGUCCACCACGAGUC 254 863 UCGUGGUGGACUUCUCUCA 904
UGAGAGAAGUCCACCACGA 374 864 UGGAUGUGUCUGCGGCGUU 905
AACGCCGCAGACACAUCCA 1575 865 CCGUGUGCACUUCGCUUCA 906
UGAAGCGAAGUGCACACGG 1577 866 GUGUGCACUUCGCUUCACC 907
GGUGAAGCGAAGUGCACAC 1578 867 UGUGCACUUCGCUUCACCU 908
AGGUGAAGCGAAGUGCACA 1579 868 GUGCACUUCGCUUCACCUC 909
GAGGUGAAGCGAAGUGCAC 1581 869 GCACUUCGCUUCACCUCUG 910
CAGAGGUGAAGCGAAGUGC 247 870 UCUAGACUCGUGGUGGACU 911
AGUCCACCACGAGUCUAGA 248 871 CUAGACUCGUGGUGGACUU 912
AAGUCCACCACGAGUCUAG 249 872 UAGACUCGUGGUGGACUUC 913
GAAGUCCACCACGAGUCUA 250 873 AGACUCGUGGUGGACUUCU 914
AGAAGUCCACCACGAGUCU 1776 874 GGAGGCUGUAGGCAUAAAU 915
AUUUAUGCCUACAGCCUCC 1777 875 GAGGCUGUAGGCAUAAAUU 916
AAUUUAUGCCUACAGCCUC 1779 876 GGCUGUAGGCAUAAAUUGG 917
CCAAUUUAUGCCUACAGCC 1780 877 GCUGUAGGCAUAAAUUGGU 918
ACCAAUUUAUGCCUACAGC 1781 878 CUGUAGGCAUAAAUUGGUC 919
GACCAAUUUAUGCCUACAG 1782 879 UGUAGGCAUAAAUUGGUCU 920
AGACCAAUUUAUGCCUACA 256 880 GUGGUGGACUUCUCUCAAU 921
AUUGAGAGAAGUCCACCAC 1863 881 UUCAAGCCUCCAAGCUGUG 922
CACAGCUUGGAGGCUUGAA 1864 882 UCAAGCCUCCAAGCUGUGC 923
GCACAGCUUGGAGGCUUGA 1865 883 CAAGCCUCCAAGCUGUGCC 924
GGCACAGCUUGGAGGCUUG 1866 884 AAGCCUCCAAGCUGUGCCU 925
AGGCACAGCUUGGAGGCUU 376 885 GAUGUGUCUGCGGCGUUUU 926
AAAACGCCGCAGACACAUC 378 886 UGUGUCUGCGGCGUUUUAU 927
AUAAAACGCCGCAGACACA 380 887 UGUCUGCGGCGUUUUAUCA 928
UGAUAAAACGCCGCAGACA 1818 888 AACUUUUUCACCUCUGCCU 929
AGGCAGAGGUGAAAAAGUU 244 889 GAGUCUAGACUCGUGGUGG 930
CCACCACGAGUCUAGACUC 245 890 AGUCUAGACUCGUGGUGGA 931
UCCACCACGAGUCUAGACU 246 891 GUCUAGACUCGUGGUGGAC 932
GUCCACCACGAGUCUAGAC 409 892 CAUCCUGCUGCUAUGCCUC 933
GAGGCAUAGCAGCAGGAUG 411 893 UCCUGCUGCUAUGCCUCAU 934
AUGAGGCAUAGCAGCAGGA 412 894 CCUGCUGCUAUGCCUCAUC 935
GAUGAGGCAUAGCAGCAGG 413 895 CUGCUGCUAUGCCUCAUCU 936
AGAUGAGGCAUAGCAGCAG 414 896 UGCUGCUAUGCCUCAUCUU 937
AAGAUGAGGCAUAGCAGCA 252 897 ACUCGUGGUGGACUUCUCU 938
AGAGAAGUCCACCACGAGU 253 898 CUCGUGGUGGACUUCUCUC 939
GAGAGAAGUCCACCACGAG 1576 899 CGUGUGCACUUCGCUUCAC 940
GUGAAGCGAAGUGCACACG 1580 900 UGCACUUCGCUUCACCUCU 941
AGAGGUGAAGCGAAGUGCA 1582 901 CACUUCGCUUCACCUCUGC 942
GCAGAGGUGAAGCGAAGUG
UNA Oligomers Targeting HBV
[0237] Embodiments of this invention can provide oligomeric
molecules that are active agents targeted to HBV.
[0238] Examples of UNA oligomers of this invention that are
targeted to an HBV component are shown in Table 17. Table 17 shows
"sense" and "antisense" pairs.
TABLE-US-00018 TABLE 17 UNA oligomers targeted to HBV (Sense (S)-
Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO
S/AS (5'-3') 244 943 S UNA-G/mAGmUCmUAmGACUmCGmUGmGUm GG/UNA-U/mU
244 944 AS mCCmACmCAmCGmAGmUmCmUAmGAmCUm C/UNA-U/mU 245 945 S
UNA-A/mGUmCUmAGmACUCmGUmGGmUGm GA/UNA-U/mU 245 946 AS
mUCmCAmCCmACmGAmGmUmCUmAGmACm U/UNA-U/mU 246 947 S
UNA-G/mUCmUAmGAmCUCGmUGmGUmGGm AC/UNA-U/mU 246 948 AS
mGUmCCmACmCAmCGmAmGmUCmUAmGAm C/UNA-U/mU 247 949 S
UNA-U/mCUmAGmACmUCGUmGGmUGmGAm CU/UNA-U/mU 247 950 AS
mAGmUCmCAmCCmACmGmAmGUmCUmAGm A/UNA-U/mU 248 951 S
UNA-C/mUAmGAmCUmCGUGmGUmGGmACm UU/UNA-U/mU 248 952 AS
mAAmGUmCCmACmCAmCmGmAGmUCmUAm G/UNA-U/mU 249 953 S
UNA-U/mAGmACmUCmGUGGmUGmGAmCUm UC/UNA-U/mU 249 954 AS
mGAmAGmUCmCAmCCmAmCmGAmGUmCUm A/UNA-U/mU 250 955 S
UNA-A/mGAmCUmCGmUGGUmGGmACmUUm CU/UNA-U/mU 250 956 AS
mAGmAAmGUmCCmACmCmAmCGmAGmUCm U/UNA-U/mU 251 957 S
UNA-G/mACmUCmGUmGGUGmGAmCUmUCm UC/UNA-U/mU 251 958 AS
mGAmGAmAGmUCmCAmCmCmACmGAmGUm C/UNA-U/mU 252 959 S
UNA-A/mCUmCGmUGmGUGGmACmUUmCUm CU/UNA-U/mU 252 960 AS
mAGmAGmAAmGUmCCmAmCmCAmCGmAGm U/UNA-U/mU 253 961 S
UNA-C/mUCmGUmGGmUGGAmCUmUCmUCm UC/UNA-U/mU 253 962 AS
mGAmGAmGAmAGmUCmCmAmCCmACmGAm G/UNA-U/mU 254 963 S
UNA-U/mCGmUGmGUmGGACmUUmCUmCUm CA/UNA-U/mU 254 964 AS
mUGmAGmAGmAAmGUmCmCmACmCAmCGm A/UNA-U/mU 256 965 S
UNA-G/mUGmGUmGGmACUUmCUmCUmCAm AU/UNA-U/mU 256 966 AS
mAUmUGmAGmAGmAAmGmUmCCmACmCAm C/UNA-U/mU 374 967 5
UNA-U/mGGmAUmGUmGUCUmGCmGGmCGm UU/UNA-U/mU 374 968 AS
mAAmCGmCCmGCmAGmAmCmACmAUmCCm A/UNA-U/mU 376 969 S
UNA-G/mAUmGUmGUmCUGCmGGmCGmUUm UU/UNA-U/mU 376 970 AS
mAAmAAmCGmCCmGCmAmGmACmACmAUm C/UNA-U/mU 378 971 S
UNA-U/mGUmGUmCUmGCGGmCGmUUmUUm AU/UNA-U/mU 378 972 AS
mAUmAAmAAmCGmCCmGmCmAGmACmACm A/UNA-U/mU 380 973 S
UNA-U/mGUmCUmGCmGGCGmUUmUUmAUm CA/UNA-U/mU 380 974 AS
mUGmAUmAAmAAmCGmCmCmGCmAGmACm A/UNA-U/mU 409 975 S
UNA-C/mAUmCCmUGmCUGCmUAmUGmCCm UC/UNA-U/mU 409 976 AS
mGAmGGmCAmUAmGCmAmGmCAmGGmAUm G/UNA-U/mU 411 977 S
UNA-U/mCCmUGmCUmGCUAmUGmCCmUCm AU/UNA-U/mU 411 978 AS
mAUmGAmGGmCAmUAmGmCmAGmCAmGGm A/UNA-U/mU 412 979 S
UNA-C/mCUmGCmUGmCUAUmGCmCUmCAm UC/UNA-U/mU 412 980 AS
mGAmUGmAGmGCmAUmAmGmCAmGCmAGm G/UNA-U/mU 413 981 S
UNA-C/mUGmCUmGCmUAUGmCCmUCmAUm CU/UNA-U/mU 413 982 AS
mAGmAUmGAmGGmCAmUmAmGCmAGmCAm G/UNA-U/mU 414 983 S
UNA-U/mGCmUGmCUmAUGCmCUmCAmUCm UU/UNA-U/mU 414 984 AS
mAAmGAmUGmAGmGCmAmUmAGmCAmGCm A/UNA-U/mU 1525 985 S
UNA-C/mGCmACmCUmCUCUmUUmACmGCm GG/UNA-U/mU 1525 986 AS
mCCmGCmGUmAAmAGmAmGmAGmGUmGCm G/UNA-U/mU 1575 987 S
UNA-C/mCGmUGmUGmCACUmUCmGCmUUm CA/UNA-U/mU 1575 988 AS
mUGmAAmGCmGAmAGmUmGmCAmCAmCGm G/UNA-U/mU 1576 989 S
UNA-C/mGUmGUmGCmACUUmCGmCUmUCm AC/UNA-U/mU 1576 990 AS
mGUmGAmAGmCGmAAmGmUmGCmACmACm G/UNA-U/mU 1577 991 S
UNA-G/mUGmUGmCAmCUUCmGCmUUmCAm CC/UNA-U/mU 1577 992 AS
mGGmUGmAAmGCmGAmAmGmUGmCAmCAm C/UNA-U/mU 1578 993 S
UNA-U/mGUmGCmACmUUCGmCUmUCmACm CU/UNA-U/mU 1578 994 AS
mAGmGUmGAmAGmCGmAmAmGUmGCmACm A/UNA-U/mU 1579 995 S
UNA-G/mUGmCAmCUmUCGCmUUmCAmCCm UC/UNA-U/mU 1579 996 AS
mGAmGGmUGmAAmGCmGmAmAGmUGmCAm C/UNA-U/mU 1580 997 5
UNA-U/mGCmACmUUmCGCUmUCmACmCUm CU/UNA-U/mU 1580 998 AS
mAGmAGmGUmGAmAGmCmGmAAmGUmGCm A/UNA-U/mU 1581 999 S
UNA-G/mCAmCUmUCmGCUUmCAmCCmUCm UG/UNA-U/mU 1581 1000 AS
mCAmGAmGGmUGmAAmGmCmGAmAGmUGm C/UNA-U/mU 1582 1001 S
UNA-C/mACmUUmCGmCUUCmACmCUmCUm GC/UNA-U/mU 1582 1002 AS
mGCmAGmAGmGUmGAmAmGmCGmAAmGUm G/UNA-U/mU 1776 1003 S
UNA-G/mGAmGGmCUmGUAGmGCmAUmAAm AU/UNA-U/mU 1776 1004 AS
mAUmUUmAUmGCmCUmAmCmAGmCCmUCm C/UNA-U/mU 1777 1005 S
UNA-G/mAGmGCmUGmUAGGmCAmUAmAAm UU/UNA-U/mU 1777 1006 AS
mAAmUUmUAmUGmCCmUmAmCAmGCmCUm C/UNA-U/mU 1779 1007 S
UNA-G/mGCmUGmUAmGGCAmUAmAAmUUm GG/UNA-U/mU 1779 1008 AS
mCCmAAmUUmUAmUGmCmCmUAmCAmGCm C/UNA-U/mU 1780 1009 S
UNA-G/mCUmGUmAGmGCAUmAAmAUmUGm GU/UNA-U/mU 1780 1010 AS
mACmCAmAUmUUmAUmGmCmCUmACmAGm C/UNA-U/mU 1781 1011 S
UNA-C/mUGmUAmGGmCAUAmAAmUUmGGm UC/UNA-U/mU 1781 1012 AS
mGAmCCmAAmUUmUAmUmGmCCmUAmCAm G/UNA-U/mU 1782 1013 S
UNA-U/mGUmAGmGCmAUAAmAUmUGmGUm CU/UNA-U/mU 1782 1014 AS
mAGmACmCAmAUmUUmAmUmGCmCUmACm A/UNA-U/mU 1818 1015 S
UNA-A/mACmUUmUUmUCACmCUmCUmGCm CU/UNA-U/mU 1818 1016 AS
mAGmGCmAGmAGmGUmGmAmAAmAAmGUm U/UNA-U/mU 1863 1017 S
UNA-U/mUCmAAmGCmCUCCmAAmGCmUGm UG/UNA-U/mU 1863 1018 AS
mCAmCAmGCmUUmGGmAmGmGCmUUmGAm A/UNA-U/mU 1864 1019 S
UNA-U/mCAmAGmCCmUCCAmAGmCUmGUm GC/UNA-U/mU 1864 1020 AS
mGCmACmAGmCUmUGmGmAmGGmCUmUGm A/UNA-U/mU 1865 1021 S
UNA-C/mAAmGCmCUmCCAAmGCmUGmUGm CC/UNA-U/mU 1865 1022 AS
mGGmCAmCAmGCmUUmGmGmAGmGCmUUm G/UNA-U/mU 1866 1023 S
UNA-A/mAGmCCmUCmCAAGmCUmGUmGCm CU/UNA-U/mU
1866 1024 AS mAGmGCmACmAGmCUmUmGmGAmGGmCUm U/UNA-U/mU
UNA Oligomers Targeting HBV
[0239] Embodiments of this invention can provide oligomeric
molecules that are active agents targeted to HBV.
[0240] Examples of UNA oligomers of this invention that are
targeted to an HBV component are shown in Table 18. Table 18 shows
"sense" and "antisense" pairs.
TABLE-US-00019 TABLE 18 UNA oligomers targeted to HBV (Sense (S)-
Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO
S/AS (5'-3') 1576 1025 S UNA-C/mGrUmGrUmGrCmArCrUrUm
CrGmCrUmUrCmArC/UNA-U/mU 1576 1026 AS mGrUmGrAmArGmC/UNA-G/mArAm
GmUmGrCmArCmArCmG/UNA-U/mU 1576 1027 S UNA-C*/mGrUmGrUmGrCmArCrUrUm
CrGmCrUmUrCmArC*/UNA-U*/mU 1576 1028 AS
mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576 1029 S
UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmArC*/UNA-U*/mU 1576 1030
AS mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576 1031
S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmA*rC*/UNA-U*/mU 1576
1032 AS mGrUmGrAmArGmC/UNA-G/mArAmGm UmGrCmArCmArCmG/UNA-U*/mU 1576
1033 S UNA-C*/mGrUmGrUmGrCmArCrUrUm CrGmCrUmUrCmArC*/UNA-U*/mU 1576
1034 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU
1576 1035 S UNA-C*/mG*rUmGrUmGrCmArCrUrUm
CrGmCrUmUrCmArC*/UNA-U*/mU 1576 1036 AS
mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1576 1037
S UNA-C*/mG*rU*mGrUmGrCmArCrUr UmCrGmCrUmUrCmArC*/UNA-U*/mU 1576
1038 AS mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU
1576 1039 S UNA-C*/mG*rU*mGrUmGrCmArCrUr
UmCrGmCrUmUrCmA*rC*/UNA-U*/mU 1576 1040 AS
mG*rU*mGrAmArGmC/UNA-G/mArAm GmUmGrCmArCmArCmG*/UNA-U*/mU 1575 1041
S UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU 1575
1042 AS mUrGmArA/UNA-G/rCmGrAmArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU 1575
1043 S UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU
1575 1044 AS mUrGmArAmGrC/UNA-G/rAmArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU
1575 1045 S UNA-C*/mC*rGmUrGmUrGmCrArCr
UmUrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1046 AS
mUrGmArAmGrCmG/UNA-A/mArGmUm GmCrAmCrAmCrGmG/UNA-U*/mU 1578 1047 S
UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmC*rU*/UNA-U*/mU 1578
1048 AS mArGmGrU/UNA-G/rAmArGmCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu 1578
1049 S UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmC*rU*/UNA-U*/mU
1578 1050 AS mArGmGrUmG/UNA-A/mArGmCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu
1578 1051 S UNA-U*/mG*rU*mGrCmArCmUrUrCr
GmCrUmUrCmArCmC*rU*/UNA-U*/mU 1578 1052 AS
mArGmGrUmGrAmA/UNA-G/mCrGmAm AmGrUmGrCmArCmA/UNA-U*/mu 1818 1053 S
UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1054 AS
mArGmGrC/UNA-A/rGmArGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 1818 1055 S
UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1056 AS
mArGmGrCmA/UNA-G/mArGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 1818 1057 S
UNA-A/mArCmUrUmUrUmUrCrArCm CrUmCrUmGrCmCrU/UNA-U/mU 1818 1058 AS
mArGmGrCmArG/UNA-A/rGmGrUm GmAmArAmArAmGrUmU/UNA-U/mU 245 1059 S
UNA-A/mGrUmCrUmArGmArCrUrCm GrUmGrGmUrGmGrA/UNA-U/mU 245 1060 AS
mUrCmCrAmCrC/-UNA-A/rCmGrAm GmUmCrUmArGmArCmU/UNA-U/mU 1580 1061 S
UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1062 AS
mArGmArG/UNA-G/rUmGrAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1063 S
UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1064 AS
mArGmArGmG/UNA-U/mGrAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1065 S
UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1066 AS
mArGmArGmGrU/UNA-G/rAmArGm CmGmArAmGrUmGrCmA/UNA-U/mU 1580 1067 S
UNA-U/mGrCmArCmUrUmCrGrCrUm UrCmArCmCrUmCrU/UNA-U/mU 1580 1068 AS
mArGmArGmGrUmG/UNA-A/mArGm CmGmArAmGrUmGrCmA/UNA-U/mU
UNA Oligomers Targeting HBV
[0241] Embodiments of this invention can provide oligomeric
molecules that are active agents targeted to HBV.
[0242] Examples of UNA oligomers of this invention that are
targeted to an HBV component are shown in Table 19. Table 19 shows
"sense" and "antisense" pairs.
TABLE-US-00020 TABLE 19 UNA oligomers targeted to HBV(Sense (S)-
Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO
S/AS (5'-3') 1578 1069 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr
UmUrCmArCmCrU*/UNA-U*/mU 1578 1070 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm
GrCmArCmA/UNA-U*/mu 1578 1071 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm
CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1072 AS
mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1073 S
UNA-U*/mG*rU*mGrCmArCmUrUrCr GmCrUmUrCmArCmCrU*/UNA-U*/mU 1578 1074
AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1075 S
UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578
1076 AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1077
S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1078
AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1079 S
UNA-U*/mG*rUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578 1080
AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1081 S
UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1082
AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578 1083 S
UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578
1084 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U*/mu 1578
1085 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578
1086 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578
1087 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU
1578 1088 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu
1578 1089 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm
CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1090 AS
mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1091 S
UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578
1092 AS mA*rGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578
1093 S UNA-U*/mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU*/UNA-U*/mU 1578
1094 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGr UmGrCmArCmA*/UNA-U*/mu 1578
1095 S UNA-U*/mG*rUmGrCmArCmUrUrCrGm CrUmUrCmArCmCrU*/UNA-U*/mU
1578 1096 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu
1578 1097 S UNA-U*/mG*rU*mGrCmArCmUrUrCrGm
CrUmUrCmArCmCrU*/UNA-U*/mU 1578 1098 AS
mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1578 1099 S
UNA-U*/mG*rU*mGrCmArCmUrUrCrGm CrUmUrCmArCmC*rU*/UNA-U*/mU 1578
1100 AS mA*rG*mGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA*/UNA-U*/mu 1777
1101 S UNA-G*/mArGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU 1777
1102 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrUmC/UNA-U*/mU 1777 1103
S UNA-G*/mA*rGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU 1777
1104 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrUmC*/UNA-U*/mU 1777
1105 S UNA-G*/mA*rG*mGrCmUrGmUrArGrGmCr AmUrAmArAmUrU*/UNA-U*/mU
1777 1106 AS mArAmUrUmUrAmUrGmCrCmUmAmCrAmGr CmCrU*mC*/UNA-U*/mU
380 1107 S UNA-U*/mGrUmCrUmGrCmGrGrCrGmUrUm UrUmArUmCrA*/UNA-U*/mU
380 1108 AS mUrGmArUmArAmArAmCrGmCmCmGrCmAr GmArCmA/UNA-U*/mU 380
1109 S UNA-U*/mG*rUmCrUmGrCmGrGrCrGmUr UmUrUmArUmCrA*/UNA-U*/mU 380
1110 AS mUrGmArUmArAmArAmCrGmCmCmGrCmAr GmArCmA/UNA-U*/mU 380 1111
S UNA-U*/mGrUmCrUmGrCmGrGrCrGmUr UmUrUmArUmCrA*/UNA-U*/mU 380 1112
AS mU*rGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U*/mU 380 1113 S
UNA-U*/mG*rU*mCrUmGrCmGrGrCrGm UrUmUrUmArUmC*rA*/UNA-U*/mU 380 1114
AS mU*rGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U*/mU 1576 1115 S
UNA-C*/mGrUmGrUmGrCmArCrUrUmCr GmCrUmUrCmArC*/UNA-U*/mU 1576 1116
AS mGrUmGrAmArGmCrGmArAmGmUmGrCm ArCmArCmG/UNA-U*/mU 1575 1117 S
UNA-C*/mC*rGmUrGmUrGmCrArCrUm UrCmGrCmUrUmCrA*/UNA-U*/mU 1575 1118
AS mUrGmArAmGrCmGrAmArGmUmGmCrAm CrAmCrGmG/UNA-U*/mU 1580 1119 S
UNA-U*/mG*rC*mArCmUrUmCrGrCrUm UrCmArCmCrUmCrU*/UNA-U*/mU 1580 1120
AS mArGmArGmGrUmGrAmArGmCmGmArAm GrUmGrCmA*/UNA-U*/mU
[0243] UNA Oligomers Targeting HBV
[0244] Embodiments of this invention can provide oligomeric
molecules that are active agents targeted to HBV.
[0245] Examples of UNA oligomers of this invention that are
targeted to an HBV component are shown in Table 20. Table 20 shows
"sense" and "antisense" pairs.
TABLE-US-00021 TABLE 20 UNA oligomers targeted to HBV (Sense (S)-
Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS NO
S/AS (5'-3') 1578 1121 S UNA-U/*/mGrUmGrCmArCmUrUrCrGm
CrUmUrCmArCmCrU/*/UNA-U/*/T 1578 1122 AS
mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*/T 1578 1123 S
UNA-U/*/fGrUfGrCfArCfUrUrCrGf CrUfUrCfArCfCrU/*/UNA-U/*/dT 1578
1124 AS fArGfGrUfGrAfArGfCrGfAfAfGrUf GrCfArCfA/UNA-U/*/dT 1578
1125 S UNA-U/*/rGfUrGfCrAfCfUfUfCrGf CfUfUfCrAfCfCfU/*/UNA-U/*/dT
1578 1126 AS rArGrGfUrGrArArGfCrGrArArGfUr GfCrAfCrA/UNA-U/*/dT
1578 1127 S UNA-U/*/mGfUmGfCmAfCmUfUfCfGm
CfUmUfCmAfCmCfU/*/UNA-U/*/T 1578 1128 AS
mAfGmGfUmGfAmAfGmCfGmAmAmGfUm GfCmAfCmA/UNA-U/*/T 1777 1129 S
UNA-G/*/mArGmGrCmUrGmUrArGrGm CrAmUrAmArAmUrU/*/UNA-U/*/T 1777 1130
AS UNA-G/*/mArGmGrCmUrGmUrArGrGm CrAmUrAmArAmUrU/*/UNA-U/*/T 1777
1131 S UNA-G/*/fArGfGrCfUrGfUrArGrGf CrAfUrAfArAfUrU/*/UNA-U/*/T
1777 1132 AS fArAfUrUfUrAfUrGfCrCfUfAfCrAf GrCfCrUfC/UNA-U/*/T 1777
1133 S UNA-G/*/rArGrGfCfUrGfUrArGrGf CrAfUrArArAfUfU/*/UNA-U/*/T
1777 1134 AS rArAfUfUfUrAfUrGfCfCfUrAfCrAr GfCfCfUfC/UNA-U/*/T 1777
1135 S UNA-G/*/mAfGmGfCmUfGmUfAfGfGm CfAmUfAmAfAmUfU/*/UNA-U/*/T
1777 1136 AS UNA-G/*/mAfGmGfCmUfGmUfAfGfGm
CfAmUfAmAfAmUfU/*/UNA-U/*/T 380 1137 S
UNA-G/*/mAfGmGfCmUfGmUfAfGfGm CfAmUfAmAfAmUfU/*/UNA-U/*/T 380 1138
AS mUrGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U/*/mU 380 1139 S
UNA-U/*/fGrUfCrUfGrCfGrGrCrGfU rUfUrUfArUfCrA/*/UNA-U/*/fU 380 1140
AS fUrGfArUfArAfArAfCrGfCfCfGrCfAr GfArCfA/UNA-U/*/fU 380 1141 S
UNA-U/*/rGfUfCfUrGfCrGrGfCrGfUf UfUfUrAfUfCrA/*/UNA-U/*/fU 380 1142
AS fUrGrAfUrArArArAfCrGfCfCrGfCrAr GrAfCrA/UNA-U/*/fU 380 1143 S
UNA-U/*/mGfUmCfUmGfCmGfGfCfGmUf UmUfUmAfUmCfA/*/UNA-U/*/mU 380 1144
AS UNA-U/*/mGfUmCfUmGfCmGfGfCfGmUf UmUfUmAfUmCfA/*/UNA-U/*/mU
[0246] In Tables herein, rN refers to N, which is a ribonucleotide,
mN refers to a chemically-modified 2'-OMe ribonucleotide, an
asterisk * between characters refers to a phosphorothioate linkage,
dN refers to a deoxyribonucleotide, f refers to a
2'-deoxy-2'-fluoro ribonucleotide.
[0247] Additional compounds of this invention are shown in Table
21.
TABLE-US-00022 TABLE 21 UNA oligomers targeted to HBV (Sense
(S)-Antisense (AS)) SEQ REF ID HBV (Sense (S)-Antisense (AS)) POS
NO S/AS (5'-3') 1575 1145 S UNA-C*/mCrGmUrGmUrGmCrArCrUm
UrCmGrCmUrUmCrA*/UNA-U*/dT 1575 1146 AS mUrGmArAmGrCmGrAmArGmUmGmCr
AmCrAmCrGmG/UNA-U*/dT 1576 1147 S UNA-C*/mGrUmGrUmGrCmArCrUrUm
CrGmCrUmUrCmArC*/UNA-U*/dT 1576 1148 AS mGrUmGrAmArGmCrGmArAmGmUmGr
CmArCmArCmG/UNA-U*/dT 1581 1149 S UNA-G*/mCAmCUmUCmGCUUmCAmCC
mUCmUG*/UNA-U*/dT 1581 1150 AS mCAmGAmGGmUGmAAmGmCmGAmAGmUG
mC/UNA-U*/dT 1580 1151 S UNA-U*/mGrCmArCmUrUmCrGrCrUm
UrCmArCmCrUmCrU*/UNA-U*/dT 1580 1152 AS mArGmArGmGrUmGrAmArGmCmGmAr
AmGrUmGrCmA/UNA-U*/dT 376 1153 A UNA-G*/mAUmGUmGUmCUGCmGGmCG
mUUmUU*/UNA-U*/dT 376 1154 AS mAAmAAmCGmCCmGCmAmGmACmAC
mAUmC/UNA-U*/dT 378 1155 S UNA-U*/mGUmGUmCUmGCGGmCGm
UUmUUmAU*/UNA-U*/dT 378 1156 AS mAUmAAmAAmCGmCCmGmCmAGmAC
mACmA/UNA-U*/dT 380 1157 S UNA-U/*mGrUmCrUmGrCmGrGrCrG
mUrUmUrUmArUmCrA/*UNA-U/*dT 380 1158 AS mUrGmArUmArAmArAmCrGmCmCmGr
CmArGmArCmA/UNA-U/*dT 413 1159 S UNA-C/*mUGmCUmGCmUAUGmCCmUC
mAUmCU/*UNA-U/*dT 413 1160 AS mAGmAUmGAmGGmCAmUmAmGCmAGm
CAmG/UNA-U/*dT 411 1161 S UNA-U/*mCCmUGmCUmGCUAmUGm
CCmUCmAU/*UNA-U/*dT 411 1162 AS mAUmGAmGGmCAmUAmGmCmAGmCA
mGGmA/UNA-U/*dT 1777 1163 S UNA-G/*mArGmGrCmUrGmUrArGrGm
CrAmUrAmArAmUrU/*UNA-U/*dT 1777 1164 AS mArAmUrUmUrAmUrGmCrCmUmAmCr
AmGrCmCrUmC/UNA-U/*dT 1780 1165 S UNA-G/*mCUmGUmAGmGCAUmAAmA
UmUGmGU/*UNA-U/*dT 1780 1166 AS mACmCAmAUmUUmAUmGmCmCUmAC
mAGmC/UNA-U/*dT 1781 1167 S UNA-C/*mUGmUAmGGmCAUAmAAm
UUmGGmUC/*UNA-U/*dT 1781 1168 AS mGAmCCmAAmUUmUAmUmGmCCmUA
mCAmG/UNA-U/*dT 1782 1169 S UNA-U/*mGUmAGmGCmAUAAmAUm
UGmGUmCU/*UNA-U/*dT 1782 1170 AS mAGmACmCAmAUmUUmAmUmGCm
CUmACmA/UNA-U/*dT
[0248] Compositions for Use Against HBV
[0249] Embodiments of this invention can provide compositions of
oligomeric molecules that are active agents targeted to HBV.
[0250] A composition for use against HBV viral infection can
provide targeting for suppressing multiple viral gene products.
[0251] Without wishing to be bound by any one particular theory,
certain open reading frames (ORF) encoding the P, S, C, and X genes
of HBV can overlap.
[0252] In some embodiments, a composition of this invention may
contain an oligomeric compound targeted to an HBV genomic
transcript or ORF for HBsAg. For example, these embodiments can
inhibit expression of HBsAg, regardless of the location of the HBV
genomic DNA.
[0253] In additional embodiments, a composition may contain an
oligomeric compound targeted to an HBV genomic transcript or ORF
for HBeAg.
[0254] In further embodiments, a composition may contain an
oligomeric compound targeted to an HBV genomic transcript or ORF
for X protein.
[0255] In further embodiments, a composition may contain an
oligomeric compound targeted to an HBV genomic transcript or ORF
for DNA polymerase (P).
[0256] In certain embodiments, a composition may contain an
oligomeric compound targeted to a conserved HBV genomic region of
the transcripts or open reading frames from genes X, S, and C.
[0257] In certain embodiments, a composition may contain an
oligomeric compound targeted to a conserved HBV genomic region of
the transcripts or open reading frames from genes X, S, C and
P.
[0258] In some aspects, a composition of this invention includes a
dyad of oligomeric compounds as the active agents targeted to
HBV.
[0259] Examples of dyad compositions include a composition
containing a compound with a reference position in the range 1403
to 1623, and a compound with a reference position in the range 155
to 550.
[0260] Examples of dyad compositions include a composition
containing a compound with a reference position in the range 1575
to 1581, and a compound with a reference position in the range 245
to 414.
[0261] Examples of dyad compositions include a composition
containing a compound with a reference position in the range 1525
to 1604, and a compound with a reference position in the range 374
to 414.
[0262] Examples of dyad compositions include a composition
containing a compound with a reference position in the range 1525
to 1604, and a compound with a reference position in the range 1776
to 1818.
[0263] Examples of dyad compositions include a composition
containing a compound with a reference position in the range 374 to
414, and a compound with a reference position in the range 1776 to
1782.
[0264] Examples of dyad compositions include a composition
containing a compound with the reference position 1578 and a
compound with the reference position 380. Examples of dyad
compositions include a composition containing a compound with the
reference position 1578 and a compound with the reference position
376 or 411.
[0265] Examples of dyad compositions include compositions
containing compounds with the reference positions 1575 and 376,
1575 and 380, 1575 and 511, 1581 and 376, 1581 and 380, as well as
1581 and 411.
[0266] Examples of dyad compositions include compositions
containing a compound with the reference position 1578 and a
compound with the reference position 1777.
[0267] Examples of dyad compositions include compositions
containing compounds with the reference positions 1578 and 1780, or
1578 and 1782, or 1575 and 1777, or 1575 and 1780, or 1575 and
1782, or 1581 and 1777, or 1581 and 1780, or 1581 and 1782, or 1576
and 1777, or 1576 and 1780, or 1576 and 1782.
[0268] For example, a dyad composition may contain the compounds
1578 and 380 shown in Table 22.
TABLE-US-00023 TABLE 22 Dyad composition of UNA oligomers targeted
to HBV (Sense (S)-Antisense (AS)) SEQ REF ID HBV (Sense
(S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1171 S
UNA-U/*mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU/*UNA-U/*dT 1578 1172
AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*dT 380 1173 S
UNA-U/*mGrUmCrUmGrCmGrGrCrGm UrUmUrUmArUmCrA/*UNA-U/*mU 380 1174 AS
mUrGmArUmArAmArAmCrGmCmCmGr CmArGmArCmA/UNA-U/*mU
UNA Oligomer Triad Compositions for HBV
[0269] In some aspects, a composition of this invention includes
triads of oligomeric compounds as the active agents targeted to
HBV.
[0270] Examples of triad compositions include a composition
containing a compound with a reference position in the range 1403
to 1623, a compound with a reference position in the range 155 to
550, and a compound with a reference position in the range 1624 to
1930.
[0271] Examples of triad compositions include a composition
containing a compound with a reference position in the range 1525
to 1582, a compound with a reference position in the range 245 to
414, and a compound with a reference position in the range 1777 to
1818.
[0272] Examples of triad compositions include a composition
containing a compound with a reference position in the range 1525
to 1604, a compound with a reference position in the range 374 to
414, and a compound with a reference position in the range 1776 to
1782.
[0273] Examples of triad compositions include a composition
containing a compound with a reference position in the range 1525
to 1582, a compound with a reference position in the range 374 to
414, and a compound with a reference position in the range 1776 to
1782.
[0274] Examples of triad compositions include a composition
containing a compound with the reference position 1578, a compound
with the reference position 380, and a compound with the reference
position 1777.
[0275] Examples of triad compositions include a composition
containing a compound with the reference position 1576, a compound
with the reference position 380, and a compound with the reference
position 1777.
[0276] Examples of triad compositions include a composition
containing a compound with the reference position 1575, a compound
with the reference position 380, and a compound with the reference
position 1777.
[0277] Examples of triad compositions include a composition
containing a compound with the reference position 1578, a compound
with the reference position 1777, and a compound with the reference
position 376 or 411.
[0278] Examples of triad compositions include a composition
containing a compound with the reference position 1578, a compound
with the reference position 1780 or 1782, and a compound with the
reference position 376 or 411.
[0279] Examples of triad compositions include compositions
containing compounds with the reference positions:
1578, 1777 and 376; 1578, 1777 and 380; 1578, 1777 and 411; 1578,
1780 and 376; 1578, 1780 and 380; 1578, 1780 and 411; 1578, 1782
and 376; 1578, 1782 and 380; 1578, 1782 and 411; 1575, 1777 and
376; 1575, 1777 and 380; 1575, 1777 and 411; 1575, 1780 and 376;
1575, 1780 and 380; 1575, 1780 and 411; 1575, 1782 and 376; 1575,
1782 and 380; 1575, 1782 and 411; 1581, 1777 and 376; 1581, 1777
and 380; 1581, 1777 and 411; 1581, 1780 and 376; 1581, 1780 and
380; 1581, 1780 and 411; 1581, 1782 and 376; 1581, 1782 and 380;
1581, 1782 and 411; 1576, 1777 and 376; 1576, 1777 and 380; 1576,
1777 and 411; 1576, 1780 and 376; 1576, 1780 and 380; 1576, 1780
and 411; 1576, 1782 and 376; 1576, 1782 and 380; 1576, 1782 and
411; 1578, 1818 and 376; 1578, 1818 and 380; 1578, 1818 and 411;
1575, 1818 and 376; 1575, 1818 and 380; 1575, 1818 and 411.
[0280] For example, a triad composition may contain the compounds
1578, 380 and 1777 shown in Table 23.
TABLE-US-00024 TABLE 23 Triad composition of UNA oligomers targeted
to HBV (Sense (5)-Antisense (AS)) SEQ REF ID HBV (Sense
(S)-Antisense (AS)) POS NO S/AS (5'-3') 1578 1175 S
UNA-U/*mGrUmGrCmArCmUrUrCrGmCr UmUrCmArCmCrU/*UNA-U/*dT 1578 1176
AS mArGmGrUmGrAmArGmCrGmAmAmGrUm GrCmArCmA/UNA-U/*dT 380 1177 S
UNA-U/*mGrUmCrUmGrCmGrGrCrGm UrUmUrUmArUmCrA/*UNA-U/*dT 380 1178 AS
mUrGmArUmArAmArAmCrGmCmCmGrCm ArGmArCmA/UNA-U/*dT 1777 1179 S
UNA-G/*mArGmGrCmUrGmUrArGrGmCr AmUrAmArAmUrU/*UNA-U/*dT 1777 1180
AS mArAmUrUmUrAmUrGmCrCmUmAmCrAm GrCmCrUmC/UNA-U/*dT
[0281] In Tables herein, rN refers to N, which is a ribonucleotide,
mN refers to a chemically-modified 2'-OMe ribonucleotide, an *
between characters refers to a phosphorothioate linkage, and dN
refers to a deoxyribonucleotide.
[0282] HBV Sequences
[0283] Some examples of known sequences for HBV are shown in Table
24.
TABLE-US-00025 TABLE 24 Sequences for HBV ACC # Genotype
Description HE974383.1 A HBV genotype A2 complete genome, isolate
Mart-B74 HE974381.1 A HBV genotype A1 complete genome, isolate
Mart-B64 HE974376.1 A HBV genotype A2 complete genome, isolate
Mart-B45 HE974375.1 A HBV genotype A1 complete genome, isolate
Mart-B43 HE974374.1 A HBV genotype A2 complete genome, isolate
Mart-B42 HE974371.1 A HBV genotype A2 complete genome, isolate
Mart-B34 HE974370.1 A HBV genotype A1 complete genome, isolate
Mart-B27 HE974367.1 A HBV genotype A2 complete genome, isolate
Mart-B22 HE974365.1 A HBV genotype A1 complete genome, isolate
Mart-B16 HE974364.1 A HBV genotype A2 complete genome, isolate
Mart-B15 HE974363.1 A HBV genotype A1 complete genome, isolate
Mart-B06 HE974362.1 A HBV genotype A1 complete genome, isolate
Mart-B01 AB778116.1 A HBV genotype A gene for polymerase, complete
cds, strain: OCU01 AB299858.1 adr Hepatitis B virus subtype adr
DNA, complete genome, clone: HBVFH0204 AB176642.1 adr Hepatitis B
virus subtype ADR DNA, complete genome, isolate: HBV-115 HW390268.1
adw JP 2013537423-A/508: RNA Interference Mediated Inhibition of
Hepatitis B Virus (HBV) AM282986.1 adw Hepatitis B virus (SUBTYPE
ADW2), genotype A, complete genome D00331.1 adw HPBADW3 Hepatitis B
virus subtype ADW genomic DNA, complete genome, clone: pIDW420
D00330.1 adw HPBADW2 Hepatitis B virus subtype ADW genomic DNA,
complete genome, clone: pODW282 D00329.1 adw HPBADW1 Hepatitis B
virus subtype ADW genomic DNA, complete genome, clone: pJDW233
AB540582.1 B HBV genotype B DNA, complete genome, strain:
B0901189(NT15) AB554017.1 B HBV genotype B DNA, complete genome,
isolate: NMB09010 AB602818.1 B HBV genotype B DNA, complete genome,
isolate: AH-2 AB644287.1 C HBV genotype C DNA, complete genome,
isolate: NAB52 AB644286.1 C HBV genotype C DNA, complete genome,
isolate: NAB47 AB644284.1 C HBV genotype C DNA, complete genome,
isolate: NAB32 AB644283.1 C HBV genotype C DNA, complete genome,
isolate: NAB28 AB644281.1 C HBV genotype C DNA, complete genome,
isolate: NAB9 AB644280.1 C HBV genotype C DNA, complete genome,
isolate: NAB1 AB560662.1 C HBV genotype C DNA, complete genome,
isolate: 60PU AB560661.1 C HBV genotype C DNA, complete genome,
isolate: 58PU AB554025.1 C HBV genotype C DNA, complete genome,
isolate: MRK89073 AB554022.1 C HBV genotype C DNA, complete genome,
isolate: GRS08325 AB554021.1 C HBV genotype C DNA, complete genome,
isolate: GRS08298 AB554020.1 C HBV genotype C DNA, complete genome,
isolate: NMB09124 AB554019.1 C HBV genotype C DNA, complete genome,
isolate: NMB09122 AB554018.1 C HBV genotype C DNA, complete genome,
isolate: NMB09075 AB554015.1 C HBV genotype C DNA, complete genome,
isolate: TRF08111 AB554014.1 C HBV genotype C DNA, complete genome,
isolate: TRF08029 AB540585.1 C HBV genotype C DNA, complete genome,
strain: C0901192(NT18) AB540584.1 C HBV genotype C DNA, complete
genome, strain: C0901190(NT16) AB540583.1 C HBV genotype C DNA,
complete genome, strain: C0901177(NT3) HE974382.1 D HBV genotype D4
complete genome, isolate Mart-B70 HE974379.1 D HBV genotype D3
complete genome, isolate Mart-B58 HE974378.1 D HBV genotype D4
complete genome, isolate Mart-B50 HE974377.1 D HBV genotype D3
complete genome, isolate Mart-B47 HE974373.1 D HBV genotype D4
complete genome, isolate Mart-B37 HE974372.1 D HBV genotype D4
complete genome, isolate Mart-B36 HE815465.1 D HBV genotype D,
serotype ayw3, complete genome AB554024.1 D HBV genotype D DNA,
complete genome, isolate: GRS08538 AB554023.1 D HBV genotype D DNA,
complete genome, isolate: GRS08457 AB554016.1 D HBV genotype D DNA,
complete genome, isolate: TRF08226 AB267090.1 D Hepatitis B virus
ayw/Japan/Ehime 22-HS/2005 DNA, complete genome HE974384.1 E HBV
genotype E complete genome, isolate Mart-B84 HE974380.1 E HBV
genotype E complete genome, isolate Mart-B63 AP007262.1 E HBV
genotype E DNA, complete genome, isolate: HB-JI411F HE974369.1 F
HBV genotype F2 complete genome, isolate Mart-B26 HE974368.1 F HBV
genotype F4 complete genome, isolate Mart-B24 HE974366.1 F HBV
genotype F2 complete genome, isolate Mart-B18 AB625343.1 G HBV
genotype G DNA, complete genome, isolate: MEX921M AB625342.1 G HBV
genotype G DNA, complete genome, isolate: MEX918M AP007264.1 G HBV
genotype G DNA, complete genome, isolate: HB-JI444GF AB846650.1 H
HBV genotype H DNA, complete genome, isolate: B-MHJ9014 AB516395.1
H HBV genotype H DNA, complete genome, isolate: MEX914M AB516394.1
H HBV genotype H DNA, complete genome, isolate: MEX912M AB516393.1
H HBV genotype H DNA, complete genome, isolate: 904MEXM AP007261.1
H HBV genotype H DNA, complete genome, isolate: HB-JI260F
AB298362.1 H HBV genotype H DNA, complete genome, isolate: HBV
ST0404 AB246338.1 Ae Hepatitis B virus DNA, complete genome, clone:
Ae_JPN AB246341.1 Bj Hepatitis B virus DNA, complete genome, clone:
Bj_JPN35 AB246345.1 C Hepatitis B virus DNA, complete genome,
clone: C_JPNAT AB246347.1 D Hepatitis B virus DNA, complete genome,
clone: D_IND60
[0284] Methods for Treating HBV Disease
[0285] Methods of this invention include the treatment and
prevention of various diseases in mammalian subjects. A subject can
be a human or mammal.
[0286] In the methods of this invention, a subject in need of
treatment or prevention can be administered an effective amount of
an oligomeric compound of this invention.
[0287] An effective amount of an oligomeric compound of this
invention can be a dose ranging from 0.001 mg/kg to 50.0 mg/kg.
[0288] In the methods of this invention, target mRNA expression can
be reduced in a subject for at least 5 days. In certain
embodiments, target mRNA expression can be reduced in a subject for
at least 10 days, or 15 days.
[0289] In the methods of this disclosure, the administration of an
oligomeric compound may not result in an inflammatory response.
[0290] In further embodiments, this invention includes methods for
inhibiting expression of a target gene in a cell, by treating the
cell with an oligomeric compound of this invention.
[0291] In additional embodiments, this invention includes methods
for inhibiting expression of a target gene in a mammal, by
administering to the mammal a composition containing an oligomeric
compound of this invention.
[0292] Pharmaceutical Compositions
[0293] In some aspects, this invention provides pharmaceutical
compositions containing an oligomeric compound and a
pharmaceutically acceptable carrier.
[0294] A pharmaceutical composition can be capable of local or
systemic administration. In some aspects, a pharmaceutical
composition can be capable of any modality of administration. In
certain aspects, the administration can be intravenous,
subcutaneous, pulmonary, intramuscular, intraperitoneal, dermal,
oral, or nasal administration.
[0295] Embodiments of this invention include pharmaceutical
compositions containing an oligomeric compound in a lipid
formulation.
[0296] In some embodiments, a pharmaceutical composition may
comprise one or more lipids selected from cationic lipids, anionic
lipids, sterols, pegylated lipids, and any combination of the
foregoing.
[0297] In certain embodiments, a pharmaceutical composition can be
substantially free of liposomes.
[0298] In further embodiments, a pharmaceutical composition can
include liposomes or nanoparticles.
[0299] Some examples of lipids and lipid compositions for delivery
of an active molecule of this invention are given in
WO/2015/074085, which is hereby incorporated by reference in its
entirety.
[0300] In additional embodiments, a pharmaceutical composition can
contain an oligomeric compound within a viral or bacterial
vector.
[0301] A pharmaceutical composition of this disclosure may include
carriers, diluents or excipients as are known in the art. Examples
of pharmaceutical compositions are described, for example, in
Remington's Pharmaceutical Sciences, Mack Publishing Co. (A.R.
Gennaro ed. 1985).
[0302] Examples of excipients for a pharmaceutical composition
include antioxidants, suspending agents, dispersing agents,
preservatives, buffering agents, tonicity agents, and
surfactants.
EXAMPLES
Example 1
Luciferase Reporter Assay
[0303] Luciferase-based reporter plasmid was constructed based on
psiCHECK.TM.2 vector (Promega, Madison, Wis.). Reporter p(1-20) was
generated with oligonucleotides containing the sequence from
position 1 through 2500 relative to Eco RI digestion site cloned
into the multiple cloning region downstream of the stop codon of
the SV40 promoted Renilla luciferase gene in psiCHECK.TM.2, which
made the expression of Renilla luciferase gene under the regulation
of the artificial 3'UTR sequence. Renilla luciferase activity was
then used as an indicator of the effect of the artificial 3'UTR on
transcript stability and translation efficiency. The psiCHECK.TM.-2
Vector also contained a constitutively expressed Firefly luciferase
gene, which served as an internal control to normalize transfection
efficiency.
[0304] A total of 5,000 HepB3 cells (American Type Culture
Collection) were plated onto a well of 96-well plate one day before
the transfectrion. The cells were incubated at 37.degree. C. in 100
.mu.l of DMEM (Life Technologies, Carlsbad, Calif.) supplemented
with 0.1 mM nonessential amino acids and 10% FBS (Life
Technologies, Carlsbad, Calif.). The culture medium was changed to
90 .mu.l of fresh medium just before the transfection. The reporter
plasmid and UNA Oligomer were co-transfected with transfection
reagent, Lipofectamine.TM. 3000 (Life Technologies, Carlsbad,
Calif.) was used to transfect reporter plasmid (100 ng) and a
various amount of UNA Oligomer together with P3000 into the cells
according to manufacturer's instruction.
[0305] Dual-Luciferase Reporter Assay System (DLR assay system,
Promega, Madison, Wis.) was used to perform dual-reporter assays on
psiCHECK2 based reporter systems. Twenty-four hours after
transfection, the cells were washed gently with phosphate buffered
saline once. A 50 .mu.l well of Passive Lysis Buffer (Promega,
Madison, Wis.) was added to the cells and incubated with gentle
rocking for 20 min at room temperature. Luciferase activities were
measured using Cytation 3 imaging reader (BioTek, Winooski, Vt.)
and the effect of the UNA Oligomer on reporter expression was
calculated based on ratio of Renilla/Firefly to normalize cell
number and transfection efficiency.
Example 2
[0306] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for each of the UNA oligomeric
compounds in Table 19 designated as having Reference Position 1578
was determined to be from 77% to 97%. Thus, all of the UNA
oligomeric compounds in Table 19 having Reference Position 1578
were operable for silencing target expression.
Example 3
[0307] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for each of the UNA oligomeric
compounds in Table 19 designated as having Reference Position 1777
was determined to be from 77% to 92%. Thus, all of the UNA
oligomeric compounds in Table 19 having Reference Position 1777
were operable for silencing target expression.
Example 4
[0308] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for each of the UNA oligomeric
compounds in Table 19 designated as having Reference Position 380
was determined to be from 87% to 94%. Thus, all of the UNA
oligomeric compounds in Table 19 having Reference Position 380 were
operable for silencing target expression.
Example 5
[0309] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for the UNA oligomeric compound in
Table 19 designated as having Reference Position 1576 was
determined to be 93%. Thus, UNA oligomeric compounds having
Reference Position 1576 were operable for modulating target
expression.
Example 6
[0310] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for the UNA oligomeric compound in
Table 19 designated as having Reference Position 1575 was
determined to be 90%. Thus, UNA oligomeric compounds having
Reference Position 1575 were operable for modulating target
expression.
Example 7
[0311] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. At 1 nM concentration for 6 days, the percent
inhibition of target expression for the UNA oligomeric compound in
Table 19 designated as having Reference Position 1580 was
determined to be 95%. Thus, UNA oligomeric compounds having
Reference Position 1580 were operable for modulating target
expression.
Example 8
[0312] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. UNA oligomers of this invention in Table 17 were
found to exhibit 1050 for inhibiting target expression as shown in
Table 25.
TABLE-US-00026 TABLE 25 IC50 of UNA oligomers targeted to HBV
Reference IC50 pM Position (6 days) 244 917 245 328 246 816 248 148
251 554 252 374 253 703 254 44 256 8 376 16 378 114 380 6.7 409 328
411 58 412 298 413 123 414 363 1575 65 1576 137 1577 472 1578 63
1580 255 1581 22 1776 461 1777 26 1779 348 1780 151 1781 227 1782
177 1818 49
[0313] Thus, UNA oligomeric compounds of this invention were
operable for modulating HBV target expression. The UNA oligomeric
compounds of this invention exhibited picomolar activity in vitro
for inhibiting target expression. In some embodiments, the UNA
oligomeric compounds of this invention exhibited surprisingly high
activity in vitro of about IC50<200 pM for inhibiting target
expression.
Example 9
[0314] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a humanized PXB Mouse model of HBV infection. The UNA
oligomers of this invention exhibited profound reduction of HBV
serum infection parameters in vivo. In this study, the UNA
oligomers were contained in lipid nanoparticle formulations, -1 and
-2.
[0315] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0316] The study used an ascending dose in which mice were treated
with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg on day
8.
[0317] As shown in FIG. 2, treatment with both UNA oligomer 1576
and UNA oligomer triad (1576, 380, 177) caused a rapid and
sustained reduction in viral endpoint serum HBsAg compared to PBS
control group. (Mean.+-.SEM).
[0318] As shown in Table 26, treatment with both UNA oligomer 1576
and UNA oligomer triad (1576, 380, 177) caused a sustained
reduction in viral endpoint serum HBeAg compared to PBS control
group. (Mean.+-.SEM).
TABLE-US-00027 TABLE 26 Serum HBeAg viral endpoint HBeAg (%
control) UNA oligomer (normalized to hAlb) formulation Day 12 PBS
control 100 1576-1 48.2 1576-2 59.8 (1576, 380, 177)-1 10.5 (1576,
380, 177)-2 15.0
[0319] As shown in Table 27, treatment with both UNA oligomer 1576
and UNA oligomer triad (1576, 380, 177) caused a sustained
reduction in viral endpoint serum HBV DNA compared to PBS control
group. (Mean.+-.SEM).
TABLE-US-00028 TABLE 27 Serum HBV DNA viral endpoint HBV DNA (%
control) UNA oligomer (normalized to hAlb) formulation Day 12 PBS
control 100 1576-1 31.2 1576-2 52.4 (1576, 380, 1777)-1 4.1 (1576,
380, 1777)-2 7.7
[0320] The compositions in FIG. 2 and Tables 26 and 27 were UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).
[0321] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo. For all viral endpoints, HBsAg, HBeAg, and HBV DNA, the
treatment with UNA oligomer triad composition (1576, 380, 177) was
significantly superior to UNA oligomer 1576.
Example 10
[0322] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo. In this study, the UNA oligomers were
contained in lipid nanoparticle formulation.
[0323] The UNA oligomers were co-formulated in lipid nanoparticles
and injected intravenously into HBV-infected Phoenix Bio (PXB)
mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0324] The study used an ascending dose in which mice were
administered every 4 days, up to day 40, and viral endpoints were
monitored every 4 days through day 44.
[0325] As shown in FIG. 3, treatment with UNA oligomer triad (1576,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBsAg compared to PBS control group. (Mean.+-.SEM). The
dose-dependent response in vivo shows a pharmacological effect of
the UNA oligomer composition. The composition in FIG. 3 was UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).
[0326] As shown in FIG. 4, treatment with UNA oligomer triad (1576,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBeAg compared to PBS control group. (Mean.+-.SEM). The
dose-dependent response in vivo shows a pharmacological effect of
the UNA oligomer composition. The composition in FIG. 4 was UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).
[0327] As shown in FIG. 5, treatment with UNA oligomer triad (1576,
380, 1777) caused a rapid and sustained reduction in viral endpoint
serum HBV DNA compared to PBS control group. (Mean.+-.SEM). The
dose-dependent response in vivo shows a pharmacological effect of
the UNA oligomer composition. The composition in FIG. 5 was UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).
[0328] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 11
[0329] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo. In this study, the UNA oligomers were
contained in lipid nanoparticle formulation.
[0330] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0331] Serum viral endpoints were monitored up to 15 days after the
single injection.
[0332] As shown in FIG. 6, treatment with each of UNA oligomers
1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and
1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained
reduction in viral endpoint serum HBsAg compared to PBS control
group. (Mean.+-.SEM).
[0333] As shown in FIG. 7, treatment with each of UNA oligomers
1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and
1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained
reduction in viral endpoint serum HBeAg compared to PBS control
group. (Mean.+-.SEM).
[0334] As shown in FIG. 8, treatment with each of UNA oligomers
1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173 and 1174) and
1578 (SEQ ID NO:1175 and 1176) caused a rapid and sustained
reduction in viral endpoint serum HBV DNA compared to PBS control
group. (Mean.+-.SEM).
[0335] As shown in FIG. 9, treatment with UNA oligomer triad
composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173
and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and
sustained reduction in viral endpoint serum HBsAg compared to PBS
control group. (Mean.+-.SEM). The dose-dependent response in vivo
shows a pharmacological effect of the UNA oligomer composition.
[0336] As shown in FIG. 10, treatment with UNA oligomer triad
composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173
and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and
sustained reduction in viral endpoint serum HBeAg compared to PBS
control group. (Mean.+-.SEM). The dose-dependent response in vivo
shows a pharmacological effect of the UNA oligomer composition.
[0337] As shown in FIG. 11, treatment with UNA oligomer triad
composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173
and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and
sustained reduction in viral endpoint serum HBV DNA compared to PBS
control group. (Mean.+-.SEM). The dose-dependent response in vivo
shows a pharmacological effect of the UNA oligomer composition.
[0338] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 12
[0339] The HBV inhibitory effect in vivo for UNA oligomers was
observed in an AAV-HBV mouse model of HBV infection. The UNA
oligomers of this invention exhibited profound reduction of HBV
serum infection parameters in vivo. In general, the AAV-HBV mouse
model is a robust model for investigating HBV infection, and can
provide direct clinical pertinence for drug efficacy and potency.
In this study, the UNA oligomers were contained in lipid
nanoparticle formulation.
[0340] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into C57Bl/6 mice with
active HBV replication after AAV-mediated delivery of a recombinant
HBV genome to the liver.
[0341] The study was an ascending dose design in which mice were
treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg
on day 8.
[0342] Serum viral endpoints were monitored 15 days before, and at
least 22 days after treatment.
[0343] As shown in FIG. 12, treatment with each of UNA oligomers
380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and
1576 (SEQ ID NO:1003 and 1004) caused a rapid and sustained
reduction in viral endpoint serum HBsAg compared to PBS control
group. (Mean.+-.SEM).
[0344] As shown in FIG. 13, treatment with each of UNA oligomers
380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and
1576 (SEQ ID NO:1003 and 1004), as well as the UNA oligomer triad
composition of the same compounds (1576, 380, 1777) caused a rapid
and sustained reduction in viral endpoint serum HBeAg compared to
PBS control group. (Mean.+-.SEM). This head-to-head comparison
shows that the triad composition provided surprisingly increased
potency throughout the duration of the effect, relative to the
individual oligomers.
[0345] As shown in FIG. 14, treatment with each of UNA oligomers
380 (SEQ ID NO:973 and 974), 1777 (SEQ ID NO:1005 and 1006), and
1576 (SEQ ID NO:1003 and 1004) caused a rapid and sustained
reduction in viral endpoint serum HBV DNA compared to PBS control
group. (Mean.+-.SEM).
[0346] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 13
[0347] The HBV inhibitory effect in vivo for UNA oligomers was
observed in an AAV-HBV mouse model of HBV infection. The UNA
oligomers of this invention exhibited profound reduction of HBV
serum infection parameters in vivo. In this study, the UNA
oligomers were contained in lipid nanoparticle formulation.
[0348] The UNA oligomers were co-formulated in lipid nanoparticles
and injected intravenously into C57Bl/6 mice with active HBV
replication after AAV-mediated delivery of a recombinant HBV genome
to the liver.
[0349] The study was an ascending dose design in which mice were
treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg
on day 8.
[0350] Serum viral endpoints were monitored up to day 12 after
treatment.
[0351] As shown in FIG. 15, treatment with the UNA oligomer triad
composition (1777 (SEQ ID NO:1179 and 1180), 380 (SEQ ID NO:1173
and 1174), 1578 (SEQ ID NO:1175 and 1176)) caused a rapid and
sustained reduction in viral endpoint serum HBsAg compared to PBS
control group. (Mean.+-.SEM). The dose-dependent response in vivo
shows a pharmacological effect of the UNA oligomer composition.
[0352] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 14
[0353] The HBV inhibitory effect in vivo for UNA oligomers was
observed in an AAV-HBV mouse model of HBV infection. The UNA
oligomers of this invention exhibited profound reduction of HBV
serum infection parameters in vivo. In general, the AAV-HBV mouse
model is a robust model for investigating HBV infection, and can
provide direct clinical pertinence for drug efficacy and potency.
In this study, the UNA oligomers were contained in lipid
nanoparticle formulation.
[0354] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into C57Bl/6 mice with
active HBV replication after AAV-mediated delivery of a recombinant
HBV genome to the liver.
[0355] The study was an ascending dose design in which mice were
treated with 3 mg/kg on day 0, then 5 mg/kg on day 4, then 10 mg/kg
on day 8.
[0356] Serum viral endpoints were monitored 15 days before, and at
least 22 days after treatment.
[0357] As shown in FIG. 16, treatment with each of UNA oligomers
1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989)
caused a rapid and sustained reduction in viral endpoint serum
HBsAg compared to PBS control group. (Mean.+-.SEM).
[0358] As shown in FIG. 17, treatment with each of UNA oligomers
1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989)
caused a rapid and sustained reduction in viral endpoint serum
HBeAg compared to PBS control group. (Mean.+-.SEM).
[0359] As shown in FIG. 18, treatment with each of UNA oligomers
1578 (SEQ ID NO:993 and 994) and 1575 (SEQ ID NO:988 and 989)
caused a rapid and sustained reduction in viral endpoint serum HBV
DNA compared to PBS control group. (Mean.+-.SEM).
[0360] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 15
[0361] The HBV inhibitory effect of UNA oligomers was observed with
a psiCHECK2 assay. The percent inhibition of target expression for
UNA oligomeric compounds containing one or more 2'-deoxy-2'-fluoro
ribonucleotides was measured.
[0362] As shown in Table 28, UNA oligomeric compounds exhibited at
least 87% inhibition of target expression at 10 nM.
TABLE-US-00029 TABLE 28 Activity of UNA oligomer Relative RLuc/FLuc
UNA oligomer at 0.1 nM, 1 nM, 10 nM 1578 (SEQ ID NO: 1127 and 1128)
0.65, 0.18, 0.08 1777 (SEQ ID NO: 1135 and 1136) 0.56, 0.14, 0.13
380 (SEQ ID NO: 1143 and 1144) 0.40, 0.14, 0.13
[0363] Thus, the UNA oligomers of this invention demonstrated
advantageous HBV inhibition efficacy in vitro.
Example 16
[0364] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo. In this study, the UNA oligomers were
contained in lipid nanoparticle formulation.
[0365] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0366] As shown in Table 29, treatment with both UNA oligomers
caused a rapid and sustained reduction in viral endpoint serum
HBsAg compared to a PBS control group.
TABLE-US-00030 TABLE 29 HBsAg (% control) (normalized to hAlb) % %
% % Inhibition Inhibition Inhibition Inhibition UNA oligomer Day 5
Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM 3.3 nM 3.3 nM 3.3 nM 1580
(SEQ ID 72.0 71.0 59.0 49.0 NO: 997 and 998) 1578 (SEQ ID 70.0 59.0
39.0 25.3 NO: 993 and 994) 1575 (SEQ ID 75.0 58.0 39.0 22.2 NO: 987
and 988) 1818 (SEQ ID 55.0 56.0 56.0 17.7 NO: 1015 and 1016) 380
(SEQ ID 62.0 55.0 33.0 30.5 NO: 973 and 974) 1576 (SEQ ID 42.0 48.0
44.0 38.2 NO: 989 and 990) 1777 (SEQ ID 65.0 43.0 21.0 12.7 NO:
1005 and 1006) 1782 (SEQ ID 65.0 43.0 25.0 20.4 NO: 1013 and 1014)
1581 (SEQ ID 50.0 42.0 28.0 11.7 NO: 999 and 1000)
[0367] Thus, the UNA oligomers of this invention demonstrated
significant and unexpectedly advantageous HBV inhibition efficacy
in vivo.
Example 17
[0368] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo. In this study, the UNA oligomers were
contained in lipid nanoparticle formulation.
[0369] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0370] As shown in Table 30, treatment with a triad UNA oligomer
composition caused a rapid and sustained reduction in viral
endpoint serum HBsAg compared to a PBS control group.
TABLE-US-00031 TABLE 30 Serum HBsAg (% control) (normalized to
hAlb) % % % % UNA oligomer Inhibition Inhibition Inhibition
Inhibition composition Day 5 Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM
3.3 nM 3.3 nM 3.3 nM 380/1777/1575 82.0 67.0 39.9 28.0
380/1777/1578 82.0 70.0 47.3 33.2 380/1777/1576 79.0 64.0 44.8
29.1
[0371] The compositions in Table 30 were:
UNA oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1575 (SEQ ID NO:987 and 988)); UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1578 (SEQ ID NO:993 and 994)); and UNA
oligomer triad composition (1777 (SEQ ID NO:1005 and 1006), 380
(SEQ ID NO:973 and 974), 1576 (SEQ ID NO:989 and 990)).
[0372] Thus, the triad UNA oligomer compositions of this invention
demonstrated significant and unexpectedly advantageous HBV
inhibition efficacy in vivo.
Example 18
[0373] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo. In this study, the UNA oligomers were
contained in lipid nanoparticle formulation.
[0374] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0375] As shown in Table 31, treatment with a triad UNA oligomer
composition caused a rapid and sustained reduction in viral
endpoint serum HBsAg compared to a PBS control group, for Genotypes
Ae, Bj, C, and D.
TABLE-US-00032 TABLE 31 Serum HBsAg (% control) (normalized to
hAlb) % % % % UNA oligomer Inhibition Inhibition Inhibition
Inhibition composition Geno- Day 5 Day 10 Day 5 Day 10 (Ref. Pos.)
type 3 nM 3 nM 15 nM 15 nM 380/1777/1578 Ae 79.2 71.0 87.5 79.0
380/1777/1578 Bj 75.4 62.2 85.0 79.0 380/1777/1578 C -- 68.8 --
82.8 380/1777/1578 D 80.7 68.9 88.5 81.4
[0376] The composition in Table 31 was UNA oligomer triad
composition (1777 (SEQ ID NO:1005 and 1006), 380 (SEQ ID NO:973 and
974), 1578 (SEQ ID NO:993 and 994)).
[0377] Thus, the triad UNA oligomer compositions of this invention
demonstrated significant and unexpectedly advantageous HBV
inhibition efficacy in vivo over a range of genotypes.
Example 19
[0378] The HBV inhibitory effect in vivo for UNA oligomers was
observed in a PXB Mouse model of HBV infection. The UNA oligomers
of this invention exhibited profound reduction of HBV serum
infection parameters in vivo with phosphorothioate linkages
present. In this study, the UNA oligomers were contained in lipid
nanoparticle formulation.
[0379] The UNA oligomers were formulated or co-formulated in lipid
nanoparticles and injected intravenously into HBV-infected Phoenix
Bio (PXB) mice. The mice were Genotype: cDNA-uPA.sup.wild/+/SCID
[cDNA-uPA.sup.wild/+: B6;129SvEv-Plau, SCID: C.B-17/Icr-scid/scid
Jcl] containing human hepatocytes with an estimated replacement
index of 70% or more.
[0380] As shown in Table 32, treatment with UNA oligomers caused a
rapid and sustained reduction in viral endpoint serum HBsAg
compared to a PBS control group.
TABLE-US-00033 TABLE 32 HBsAg (% control) (normalized to hAlb) % %
% % Inhibition Inhibition Inhibition Inhibition UNA oligomer Day 5
Day 10 Day 15 Day 20 Ref. Pos. 3.3 nM 3.3 nM 3.3 nM 3.3 nM 1575
(SEQ ID 76.2 60.4 25.0 3.0 NO: 987 and 988) 1575PS (SEQ ID 79.0
77.5 58.5 35.7 NO: 1117 and 1118) 1578 (SEQ ID 77.0 65.6 34.4 5.7
NO: 993 and 994) 1578PS (SEQ ID 78.1 72.7 53.5 18.3 NO: 1069 and
1070) 380 (SEQ ID 72.4 69.5 48.1 23.9 NO: 973 and 974) 380PS (SEQ
ID 68.1 69.9 52.4 35.2 NO: 1107 and 1108)
[0381] Thus, the UNA oligomers of this invention with
phosphorothioate linkages (PS) demonstrated significant and
unexpectedly advantageous HBV inhibition efficacy in vivo with
longer duration (Day 15 to Day 20). The phosphorothioate linkages
were as follows: one phosphorothioate linkage between two monomers
at the 5' end of the first strand, one phosphorothioate linkage
between two monomers at the 3' end of the first strand, one
phosphorothioate linkage between monomers at the second and third
positions from the 3' end of the first strand, and one
phosphorothioate linkage between two monomers at the 3' end of the
second strand.
Example 20
HBV Reference Genome HB974376 (3221 bp)
TABLE-US-00034 [0382] SEQ ID NO: 1181 1 ttccactgcc ttccaccaag
ctctgcagga tcccagagtc aggggtctgt attttcctgc 61 tggtggctcc
agttcaggaa cagtaaaccc tgctccgaat attgcctctc acatctcgtc 121
aatctccgcg aggactgggg accctgtgac gaacatggag aacatcacat caggattcct
181 aggacccctg ctcgtgttac aggcggggtt tttcttgttg acaagaatcc
tcacaatacc 241 gcagagtcta gactcgtggt ggacttctct caattttcta
gggggatcac ccgtgtgtct 301 tggccaaaat tcgcagtccc caacctccaa
tcactcacca acctcctgtc ctccaatttg 361 tcctggttat cgctggatgt
gtctgcggcg ttttatcata ttcctcttca tcctgctgct 421 atgcctcatc
ttcttattgg ttcttctgga ttatcaaggt atgttgcccg tttgtcctct 481
aattccagga tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca
541 aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa
attgcacctg 601 tattcccatc ccatcgtcct gggctttcgc aaaataccta
tgggagtggg cctcagtccg 661 tttctcttgg ctcagtttac tagtgccatt
tgttcagtgg ttcgtagggc tttcccccac 721 tgtttggctt tcagctatat
ggatgatgtg gtattggggg ccaagtctgt acagcatcgt 781 gagtcccttt
ataccgctgt taccaatttt cttttgtctc tgggtataca tttaaaccct 841
aacaaaacaa aaagatgggg ttattcccta aacttcatgg gttacataat tggaagttgg
901 ggaactttgc cacaggatca tattgtacaa aagatcaaac actgttttag
aaaacttcct 961 gttaacaggc ctattgattg gaaagtatgt caaagaattg
tgggtctttt gggctttgct 1021 gctccattta cacaatgtgg atatcctgcc
ttaatgcctt tgtatgcatg tatacaagct 1081 aaacaggctt tcactttctc
gccaacttac aaggcctttc taagtaaaca gtacatgaac 1141 ctttaccccg
ttgctcggca acggcctggt ctgtgccaag tgtttgctga cgcaaccccc 1201
actggctggg gcttggccat aggccatcag cgcatgcgtg gaacctttgt ggctcctctg
1261 ccgatccata ctgcggaact cctagccgct tgttttgctc gcagccggtc
tggagcaaag 1321 ctcatcggaa ctgacaattc tgtcgtcctc tcgcggaaat
atacatcgtt tccatggctg 1381 ctaggctgta ctgccaactg gatccttcgc
gggacgtcct ttgtttacgt cccgtcggcg 1441 ctgaatcccg cggacgaccc
ctctcggggc cgcttgggac tctctcgtcc ccttctccgt 1501 ctgccgttcc
agccgaccac ggggcgcacc tctctttacg cggtctcccc gtctgtgcct 1561
tctcatctgc cggtccgtgt gcacttcgct tcacctctgc acgttgcatg gagaccaccg
1621 tgaacgccca tcagatcctg cccaaggtct tacataagag gactcttgga
ctcccagcaa 1681 tgtcaacgac cgaccttgag gcctacttca aagactgtgt
gtttaaagac tgggaggagc 1741 tgggggagga gattaggtta aaggtctttg
tattaggagg ctgtaggcat aaattggtct 1801 gcgcaccagc accatgcaac
tttttcacct ctgcctaatc atctcttgta catgtcccac 1861 tgttcaagcc
tccaagctgt gccttgggtg gctttggggc atggacattg acccttataa 1921
agaatttgga gctactgtgg agttactctc gtttttgcct tctgacttct ttccttccgt
1981 cagagatctc ctagacaccg cctcagctct gtatcgagaa gccttagaat
ctcctgagca 2041 ttgctcacct caccatactg cactcaggca agccattctc
tgctgggggg aattgatgac 2101 tctagctacc tgggtgggta ataatttgga
agatccagca tccagggatc tagtagtcaa 2161 ttatgttaat actaacatgg
gtttaaagat caggcaacta ttgtggtttc atatatcttg 2221 ccttactttt
ggaagagaga ctgtacttga atatttggtc tctttcggag tgtggattcg 2281
cactcctcca gcctatagac caccaaatgc ccctatctta tcaacacttc cggaaactac
2341 tgttgttaga cgacgggacc gaggcaggtc ccctagaaga agaactccct
cgcctcgcag 2401 acgcagatct caatcgccgc gtcgcagaag atctcaatct
cgggaatctc aatgttagta 2461 ttccttggac tcataaggtg ggaaacttta
cggggcttta ttcctctaca gtacctatct 2521 ttaatcctga atggcaaact
ccttcctttc ctaagattca tttacaagag gacattatta 2581 ataggtgtca
acaatttgtg ggccctctca ctgtaaatga aaagagaaga ttgaaattaa 2641
ttatgcctgc tagattctat cctactcaca ctaaatattt gcccttagac aaaggaatta
2701 aaccttatta tccagatcag gtagttaatc attacttcca aaccagacat
tatttacata 2761 ctctttggaa ggctggtatt ctatataaga gggaaaccac
acgtagcgca tcattttgtg 2821 ggtcaccata ttcttgggaa caagagctac
agcatgggag gttggtcatc aaaacctcgc 2881 aaaggcatgg ggacgaatct
ttctgttccc aaccctctgg gattctttcc cgatcatcag 2941 ttggaccctg
cattcggagc caactcaaac aatccagatt gggacttcaa ccccatcaag 3001
gaccactggc cagcagccaa ccaggtagga gcgggagcat tcgggccagg gctcacccct
3061 ccacacggcg gtattctggg gtggagccct caggctcagg gcatattgac
cacagtgtca 3121 acaattcctc ctcctgcctc caccaatcgg cagtcaggaa
ggcagcctac tcccatctct 3181 ccacctctaa gagacagtca tcctcaggcc
atgcagtgga a
[0383] All publications, patents and literature specifically
mentioned herein are incorporated by reference for all
purposes.
[0384] It is understood that this invention is not limited to the
particular methodology, protocols, materials, and reagents
described, as these may vary. It is also to be understood that the
terminology used herein is for the purpose of describing particular
embodiments only, and is not intended to limit the scope of the
present invention, which will be encompassed by the appended
claims.
[0385] It must be noted that as used herein and in the appended
claims, the singular forms "a", "an", and "the" include plural
reference unless the context clearly dictates otherwise. As well,
the terms "a" (or "an"), "one or more" and "at least one" can be
used interchangeably herein. It is also to be noted that the terms
"comprises," "comprising", "containing," "including", and "having"
can be used interchangeably.
[0386] Without further elaboration, it is believed that one skilled
in the art can, based on the above description, utilize the present
invention to its fullest extent. The following specific embodiments
are, therefore, to be construed as merely illustrative, and not
limitative of the remainder of the disclosure in any way
whatsoever.
[0387] All of the features disclosed in this specification may be
combined in any combination. Each feature disclosed in this
specification may be replaced by an alternative feature serving the
same, equivalent, or similar purpose.
Sequence CWU 1
1
1181122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1nnnnnnnnnn nnnnnnnnnn nn
22221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 2nnnnnnnnnn nnnnnnnnnn n
21322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 3nnnnnnnnnn nnnnnnnnnn nn
22421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 4nnnnnnnnnn nnnnnnnnnn n
21522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 5nnnnnnnnnn nnnnnnnnnn nn
22621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 6nnnnnnnnnn nnnnnnnnnn n
21722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 7nnnnnnnnnn nnnnnnnnnn nn
22821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 8nnnnnnnnnn nnnnnnnnnn n
21922RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 9nnnnnnnnnn nnnnnnnnnn nn
221021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 10nnnnnnnnnn nnnnnnnnnn n
211122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 11nnnnnnnnnn nnnnnnnnnn nn
221221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 12nnnnnnnnnn nnnnnnnnnn n
211322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 13nnnnnnnnnn nnnnnnnnnn nn
221421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 14nnnnnnnnnn nnnnnnnnnn n
211522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 15nnnnnnnnnn nnnnnnnnnn nn
221621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 16nnnnnnnnnn nnnnnnnnnn n
211722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 17nnnnnnnnnn nnnnnnnnnn nn
221821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 18nnnnnnnnnn nnnnnnnnnn n
211922RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 19nnnnnnnnnn nnnnnnnnnn nn
222021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 20nnnnnnnnnn nnnnnnnnnn n
212122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 21nnnnnnnnnn nnnnnnnnnn nn
222221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 22nnnnnnnnnn nnnnnnnnnn n
212322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 23nnnnnnnnnn nnnnnnnnnn nn
222421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 24nnnnnnnnnn nnnnnnnnnn n
212522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 25nnnnnnnnnn nnnnnnnnnn nn
222621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 26nnnnnnnnnn nnnnnnnnnn n
212722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 27nnnnnnnnnn nnnnnnnnnn nn
222821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 28nnnnnnnnnn nnnnnnnnnn n
212922RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 29nnnnnnnnnn nnnnnnnnnn nn
223021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 30nnnnnnnnnn nnnnnnnnnn n
213122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 31nnnnnnnnnn nnnnnnnnnn nn
223221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 32nnnnnnnnnn nnnnnnnnnn n
213322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 33nnnnnnnnnn nnnnnnnnnn nn
223421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 34nnnnnnnnnn nnnnnnnnnn n
213522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 35nnnnnnnnnn nnnnnnnnnn nn
223621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 36nnnnnnnnnn nnnnnnnnnn n
213722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 37nnnnnnnnnn nnnnnnnnnn nn
223821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 38nnnnnnnnnn nnnnnnnnnn n
213922RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 39nnnnnnnnnn nnnnnnnnnn nn
224021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 40nnnnnnnnnn nnnnnnnnnn n
214122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 41nnnnnnnnnn nnnnnnnnnn nn
224221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 42nnnnnnnnnn nnnnnnnnnn n
214322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 43nnnnnnnnnn nnnnnnnnnn nn
224421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 44nnnnnnnnnn nnnnnnnnnn n
214522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 45nnnnnnnnnn nnnnnnnnnn nn
224621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 46nnnnnnnnnn nnnnnnnnnn n
214722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 47nnnnnnnnnn nnnnnnnnnn nn
224821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 48nnnnnnnnnn nnnnnnnnnn n
214922RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 49nnnnnnnnnn nnnnnnnnnn nn
225021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 50nnnnnnnnnn nnnnnnnnnn n
215122RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 51nnnnnnnnnn nnnnnnnnnn nn
225221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 52nnnnnnnnnn nnnnnnnnnn n
215322RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 53nnnnnnnnnn nnnnnnnnnn nn
225421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 54nnnnnnnnnn nnnnnnnnnn n
215522RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 55nnnnnnnnnn nnnnnnnnnn nn
225621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 56nnnnnnnnnn nnnnnnnnnn n
215722RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 57nnnnnnnnnn nnnnnnnnnn nn
225821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 58nnnnnnnnnn nnnnnnnnnn n
215921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 59nnnnnnnnnn nnnnnnnnnn n
216021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 60nnnnnnnnnn nnnnnnnnnn n
216121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 61nnnnnnnnnn nnnnnnnnnn n
216221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 62nnnnnnnnnn nnnnnnnnnn n
216321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 63nnnnnnnnnn nnnnnnnnnn n
216421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 64nnnnnnnnnn nnnnnnnnnn n
216521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 65nnnnnnnnnn nnnnnnnnnn n
216621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 66nnnnnnnnnn nnnnnnnnnn n
216721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 67nnnnnnnnnn nnnnnnnnnn n
216821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 68nnnnnnnnnn nnnnnnnnnn n
216921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 69nnnnnnnnnn nnnnnnnnnn n
217021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 70nnnnnnnnnn nnnnnnnnnn n
217121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 71nnnnnnnnnn nnnnnnnnnn n
217221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 72nnnnnnnnnn nnnnnnnnnn n
217321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 73nnnnnnnnnn nnnnnnnnnn n
217421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 74nnnnnnnnnn nnnnnnnnnn n
217521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 75nnnnnnnnnn nnnnnnnnnn n
217621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 76nnnnnnnnnn nnnnnnnnnn n
217721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 77nnnnnnnnnn nnnnnnnnnn n
217821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 78nnnnnnnnnn nnnnnnnnnn n
217921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 79nnnnnnnnnn nnnnnnnnnn n
218021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 80nnnnnnnnnn nnnnnnnnnn n
218121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 81nnnnnnnnnn nnnnnnnnnn n
218221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 82nnnnnnnnnn nnnnnnnnnn n
218321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 83nnnnnnnnnn nnnnnnnnnn n
218421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 84nnnnnnnnnn nnnnnnnnnn n
218521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 85nnnnnnnnnn nnnnnnnnnn n
218621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 86nnnnnnnnnn nnnnnnnnnn n
218721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 87nnnnnnnnnn nnnnnnnnnn n
218821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 88nnnnnnnnnn nnnnnnnnnn n
218921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 89nnnnnnnnnn nnnnnnnnnn n
219021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 90nnnnnnnnnn nnnnnnnnnn n
219121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 91nnnnnnnnnn nnnnnnnnnn n
219221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 92nnnnnnnnnn nnnnnnnnnn n
219321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 93nnnnnnnnnn nnnnnnnnnn n
219421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 94nnnnnnnnnn nnnnnnnnnn n
219521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 95nnnnnnnnnn nnnnnnnnnn n
219621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 96nnnnnnnnnn nnnnnnnnnn n
219721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 97nnnnnnnnnn nnnnnnnnnn n
219821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 98nnnnnnnnnn nnnnnnnnnn n
219921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 99nnnnnnnnnn nnnnnnnnnn n
2110021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 100nnnnnnnnnn nnnnnnnnnn n
2110121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 101nnnnnnnnnn nnnnnnnnnn n
2110221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 102nnnnnnnnnn nnnnnnnnnn n
2110321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 103nnnnnnnnnn nnnnnnnnnn n
2110421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 104nnnnnnnnnn nnnnnnnnnn n
2110521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 105nnnnnnnnnn nnnnnnnnnn n
2110621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 106nnnnnnnnnn nnnnnnnnnn n
2110721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 107nnnnnnnnnn nnnnnnnnnn n
2110821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 108nnnnnnnnnn nnnnnnnnnn n
2110921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 109nnnnnnnnnn nnnnnnnnnn n
2111021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 110nnnnnnnnnn nnnnnnnnnn n
2111121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 111nnnnnnnnnn nnnnnnnnnn n
2111221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 112nnnnnnnnnn nnnnnnnnnn n
2111321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 113nnnnnnnnnn nnnnnnnnnn n
2111421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 114nnnnnnnnnn nnnnnnnnnn n
2111521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 115nnnnnnnnnn nnnnnnnnnn n
2111621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 116nnnnnnnnnn nnnnnnnnnn n
2111721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 117nnnnnnnnnn nnnnnnnnnn n
2111821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 118nnnnnnnnnn nnnnnnnnnn n
2111921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 119nnnnnnnnnn nnnnnnnnnn n
2112021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 120nnnnnnnnnn nnnnnnnnnn n
2112121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 121nnnnnnnnnn nnnnnnnnnn n
2112221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 122nnnnnnnnnn nnnnnnnnnn n
2112321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 123nnnnnnnnnn nnnnnnnnnn n
2112421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 124nnnnnnnnnn nnnnnnnnnn n
2112521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 125nnnnnnnnnn nnnnnnnnnn n
2112621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 126nnnnnnnnnn nnnnnnnnnn n
2112721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 127nnnnnnnnnn nnnnnnnnnn n
2112821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 128nnnnnnnnnn nnnnnnnnnn n
2112921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 129nnnnnnnnnn nnnnnnnnnn n
2113021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 130nnnnnnnnnn nnnnnnnnnn n
2113121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 131nnnnnnnnnn nnnnnnnnnn n
2113221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 132nnnnnnnnnn nnnnnnnnnn n
2113321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 133nnnnnnnnnn nnnnnnnnnn n
2113421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 134nnnnnnnnnn nnnnnnnnnn n
2113521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 135nnnnnnnnnn nnnnnnnnnn n
2113621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 136nnnnnnnnnn nnnnnnnnnn n
2113721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 137nnnnnnnnnn nnnnnnnnnn n
2113821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 138nnnnnnnnnn nnnnnnnnnn n
2113921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 139nnnnnnnnnn nnnnnnnnnn n
2114021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 140nnnnnnnnnn nnnnnnnnnn n
2114121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 141nnnnnnnnnn nnnnnnnnnn n
2114221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 142nnnnnnnnnn nnnnnnnnnn n
2114321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 143nnnnnnnnnn nnnnnnnnnn n
2114421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 144nnnnnnnnnn nnnnnnnnnn n
2114521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 145nnnnnnnnnn nnnnnnnnnn n
2114621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 146nnnnnnnnnn nnnnnnnnnn n
2114721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 147nnnnnnnnnn nnnnnnnnnn n
2114821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 148nnnnnnnnnn nnnnnnnnnn n
2114921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 149nnnnnnnnnn nnnnnnnnnn n
2115021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 150nnnnnnnnnn nnnnnnnnnn n
2115121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 151nnnnnnnnnn nnnnnnnnnn n
2115221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 152nnnnnnnnnn nnnnnnnnnn n
2115321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 153nnnnnnnnnn nnnnnnnnnn n
2115421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 154nnnnnnnnnn nnnnnnnnnn n
2115521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 155nnnnnnnnnn nnnnnnnnnn n
2115621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 156nnnnnnnnnn nnnnnnnnnn n
2115721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 157nnnnnnnnnn nnnnnnnnnn n
2115821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 158nnnnnnnnnn nnnnnnnnnn n
2115921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 159nnnnnnnnnn nnnnnnnnnn n
2116021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 160nnnnnnnnnn nnnnnnnnnn n
2116121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 161nnnnnnnnnn nnnnnnnnnn n
2116221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 162nnnnnnnnnn nnnnnnnnnn n
2116321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 163nnnnnnnnnn nnnnnnnnnn n
2116421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 164nnnnnnnnnn nnnnnnnnnn n
2116521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 165nnnnnnnnnn nnnnnnnnnn n
2116621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 166nnnnnnnnnn nnnnnnnnnn n
2116721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 167nnnnnnnnnn nnnnnnnnnn n
2116821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 168nnnnnnnnnn nnnnnnnnnn n
2116921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 169nnnnnnnnnn nnnnnnnnnn n
2117021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 170nnnnnnnnnn nnnnnnnnnn n
2117121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 171nnnnnnnnnn nnnnnnnnnn n
2117221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 172nnnnnnnnnn nnnnnnnnnn n
2117321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 173nnnnnnnnnn nnnnnnnnnn n
2117421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 174nnnnnnnnnn nnnnnnnnnn n
2117521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 175nnnnnnnnnn nnnnnnnnnn n
2117621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 176nnnnnnnnnn nnnnnnnnnn n
2117721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 177nnnnnnnnnn nnnnnnnnnn n
2117821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 178nnnnnnnnnn nnnnnnnnnn n
2117921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 179nnnnnnnnnn nnnnnnnnnn n
2118021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 180nnnnnnnnnn nnnnnnnnnn n
2118121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 181nnnnnnnnnn nnnnnnnnnn n
2118221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 182nnnnnnnnnn nnnnnnnnnn n
2118321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 183nnnnnnnnnn nnnnnnnnnn n
2118421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 184nnnnnnnnnn nnnnnnnnnn n
2118521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 185nnnnnnnnnn nnnnnnnnnn n
2118621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 186nnnnnnnnnn nnnnnnnnnn n
2118721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 187nnnnnnnnnn nnnnnnnnnn n
2118821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 188nnnnnnnnnn nnnnnnnnnn n
2118921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 189nnnnnnnnnn nnnnnnnnnn n
2119021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 190nnnnnnnnnn nnnnnnnnnn n
2119121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 191nnnnnnnnnn nnnnnnnnnn n
2119221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 192nnnnnnnnnn nnnnnnnnnn n
2119321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 193nnnnnnnnnn nnnnnnnnnn n
2119421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 194nnnnnnnnnn nnnnnnnnnn n
2119521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 195nnnnnnnnnn nnnnnnnnnn n
2119621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 196nnnnnnnnnn nnnnnnnnnn n
2119721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 197nnnnnnnnnn nnnnnnnnnn n
2119821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 198nnnnnnnnnn nnnnnnnnnn n
2119921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 199nnnnnnnnnn nnnnnnnnnn n
2120021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 200nnnnnnnnnn nnnnnnnnnn n
2120121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 201nnnnnnnnnn nnnnnnnnnn n
2120221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 202nnnnnnnnnn nnnnnnnnnn n
2120321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 203nnnnnnnnnn nnnnnnnnnn n
2120421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 204nnnnnnnnnn nnnnnnnnnn n
2120521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 205nnnnnnnnnn nnnnnnnnnn n
2120621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 206nnnnnnnnnn nnnnnnnnnn n
2120721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 207nnnnnnnnnn nnnnnnnnnn n
2120821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic
oligonucleotide 208nnnnnnnnnn nnnnnnnnnn n 2120921RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 209nnnnnnnnnn nnnnnnnnnn n 2121021RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 210nnnnnnnnnn nnnnnnnnnn n 2121121RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 211nnnnnnnnnn nnnnnnnnnn n 2121221RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 212nnnnnnnnnn nnnnnnnnnn n 2121321RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 213nnnnnnnnnn nnnnnnnnnn n 2121421RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 214nnnnnnnnnn nnnnnnnnnn n 2121521RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 215nnnnnnnnnn nnnnnnnnnn n 2121621RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 216nnnnnnnnnn nnnnnnnnnn n 2121721RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 217nnnnnnnnnn nnnnnnnnnn n 2121821RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 218nnnnnnnnnn nnnnnnnnnn n 2121921RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 219nnnnnnnnnn nnnnnnnnnn n 2122021RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 220nnnnnnnnnn nnnnnnnnnn n 2122121RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 221nnnnnnnnnn nnnnnnnnnn n 2122221RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 222nnnnnnnnnn nnnnnnnnnn n 2122321RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 223nnnnnnnnnn nnnnnnnnnn n 2122421RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 224nnnnnnnnnn nnnnnnnnnn n 2122521RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 225nnnnnnnnnn nnnnnnnnnn n 2122621RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 226nnnnnnnnnn nnnnnnnnnn n 2122721RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 227nnnnnnnnnn nnnnnnnnnn n 2122821RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 228nnnnnnnnnn nnnnnnnnnn n 2122921RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 229nnnnnnnnnn nnnnnnnnnn n 2123021RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 230nnnnnnnnnn nnnnnnnnnn n 2123121RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 231nnnnnnnnnn nnnnnnnnnn n 2123221RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 232nnnnnnnnnn nnnnnnnnnn n 2123321RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 233nnnnnnnnnn nnnnnnnnnn n 2123421RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 234nnnnnnnnnn nnnnnnnnnn n 2123521RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 235nnnnnnnnnn nnnnnnnnnn n 2123621RNAArtificial
SequenceDescription of Artificial Sequence Synthetic
oligonucleotide 236nnnnnnnnnn nnnnnnnnnn n 2123719RNAHepatitis B
virus 237cgcaccucuc uuuacgcgg 1923819RNAHepatitis B virus
238gacucguggu ggacuucuc 1923919RNAHepatitis B virus 239ucguggugga
cuucucuca 1924019RNAHepatitis B virus 240uggauguguc ugcggcguu
1924119RNAHepatitis B virus 241ccgugugcac uucgcuuca
1924219RNAHepatitis B virus 242gugugcacuu cgcuucacc
1924319RNAHepatitis B virus 243ugugcacuuc gcuucaccu
1924419RNAHepatitis B virus 244gugcacuucg cuucaccuc
1924519RNAHepatitis B virus 245gcacuucgcu ucaccucug
1924619RNAHepatitis B virus 246uucaagccuc caagcugug
1924719RNAHepatitis B virus 247ucaagccucc aagcugugc
1924819RNAHepatitis B virus 248caagccucca agcugugcc
1924919RNAHepatitis B virus 249aagccuccaa gcugugccu
1925019RNAHepatitis B virus 250ucuagacucg ugguggacu
1925119RNAHepatitis B virus 251cuagacucgu gguggacuu
1925219RNAHepatitis B virus 252uagacucgug guggacuuc
1925319RNAHepatitis B virus 253agacucgugg uggacuucu
1925419RNAHepatitis B virus 254gaugugucug cggcguuuu
1925519RNAHepatitis B virus 255ugugucugcg gcguuuuau
1925619RNAHepatitis B virus 256ugucugcggc guuuuauca
1925719RNAHepatitis B virus 257ggaggcugua ggcauaaau
1925819RNAHepatitis B virus 258gaggcuguag gcauaaauu
1925919RNAHepatitis B virus 259ggcuguaggc auaaauugg
1926019RNAHepatitis B virus 260gcuguaggca uaaauuggu
1926119RNAHepatitis B virus 261aacuuuuuca ccucugccu
1926219RNAHepatitis B virus 262gagucuagac ucguggugg
1926319RNAHepatitis B virus 263agucuagacu cguggugga
1926419RNAHepatitis B virus 264gucuagacuc gugguggac
1926519RNAHepatitis B virus 265cauccugcug cuaugccuc
1926619RNAHepatitis B virus 266uccugcugcu augccucau
1926719RNAHepatitis B virus 267ccugcugcua ugccucauc
1926819RNAHepatitis B virus 268cugcugcuau gccucaucu
1926919RNAHepatitis B virus 269ugcugcuaug ccucaucuu
1927019RNAHepatitis B virus 270cuguaggcau aaauugguc
1927119RNAHepatitis B virus 271uguaggcaua aauuggucu
1927219RNAHepatitis B virus 272acucguggug gacuucucu
1927319RNAHepatitis B virus 273cucguggugg acuucucuc
1927419RNAHepatitis B virus 274cgugugcacu ucgcuucac
1927519RNAHepatitis B virus 275ugcacuucgc uucaccucu
1927619RNAHepatitis B virus 276cacuucgcuu caccucugc
1927719RNAHepatitis B virus 277acuucgcuuc accucugca
1927819RNAHepatitis B virus 278agccuccaag cugugccuu
1927919RNAHepatitis B virus 279gccuccaagc ugugccuug
1928019RNAHepatitis B virus 280gaacucccuc gccucgcag
1928119RNAHepatitis B virus 281aacucccucg ccucgcaga
1928219RNAHepatitis B virus 282acucccucgc cucgcagac
1928319RNAHepatitis B virus 283cucccucgcc ucgcagacg
1928419RNAHepatitis B virus 284ccugcuggug gcuccaguu
1928519RNAHepatitis B virus 285cugcuggugg cuccaguuc
1928619RNAHepatitis B virus 286ggaugugucu gcggcguuu
1928719RNAHepatitis B virus 287augugucugc ggcguuuua
1928819RNAHepatitis B virus 288gugucugcgg cguuuuauc
1928919RNAHepatitis B virus 289gucugcggcg uuuuaucau
1929019RNAHepatitis B virus 290ccuaugggag ugggccuca
1929119RNAHepatitis B virus 291cuaugggagu gggccucag
1929219RNAHepatitis B virus 292cuucgcuuca ccucugcac
1929319RNAHepatitis B virus 293uucgcuucac cucugcacg
1929419RNAHepatitis B virus 294ucgcuucacc ucugcacgu
1929519RNAHepatitis B virus 295aggcuguagg cauaaauug
1929619RNAHepatitis B virus 296acuuuuucac cucugccua
1929719RNAHepatitis B virus 297auccugcugc uaugccuca
1929819RNAHepatitis B virus 298gcugcuaugc cucaucuuc
1929919RNAHepatitis B virus 299cugcuaugcc ucaucuucu
1930019RNAHepatitis B virus 300ugcuaugccu caucuucuu
1930119RNAHepatitis B virus 301guaggcauaa auuggucug
1930219RNAHepatitis B virus 302ccuccaagcu gugccuugg
1930319RNAHepatitis B virus 303cgugguggac uucucucaa
1930419RNAHepatitis B virus 304gugguggacu ucucucaau
1930519RNAHepatitis B virus 305ugguggacuu cucucaauu
1930619RNAHepatitis B virus 306gguggacuuc ucucaauuu
1930719RNAHepatitis B virus 307guggacuucu cucaauuuu
1930819RNAHepatitis B virus 308uggacuucuc ucaauuuuc
1930919RNAHepatitis B virus 309gacuucucuc aauuuucua
1931019RNAHepatitis B virus 310acuucucuca auuuucuag
1931119RNAHepatitis B virus 311cuucucucaa uuuucuagg
1931219RNAHepatitis B virus 312uucucucaau uuucuaggg
1931319RNAHepatitis B virus 313ucucucaauu uucuagggg
1931419RNAHepatitis B virus 314auccauacug cggaacucc
1931519RNAHepatitis B virus 315uccauacugc ggaacuccu
1931619RNAHepatitis B virus 316gaagaagaac ucccucgcc
1931719RNAHepatitis B virus 317aagaagaacu cccucgccu
1931819RNAHepatitis B virus 318agaagaacuc ccucgccuc
1931919RNAHepatitis B virus 319gaagaacucc cucgccucg
1932019RNAHepatitis B virus 320aagaacuccc ucgccucgc
1932119RNAHepatitis B virus 321agaacucccu cgccucgca
1932219RNAHepatitis B virus 322agagucuaga cucguggug
1932319RNAHepatitis B virus 323ggacuucucu caauuuucu
1932419RNAHepatitis B virus 324gauccauacu gcggaacuc
1932519RNAHepatitis B virus 325ugcaacuuuu ucaccucug
1932619RNAHepatitis B virus 326gcaacuuuuu caccucugc
1932719RNAHepatitis B virus 327caacuuuuuc accucugcc
1932819RNAHepatitis B virus 328uggccaaaau ucgcagucc
1932919RNAHepatitis B virus 329ggccaaaauu cgcaguccc
1933019RNAHepatitis B virus 330ccgauccaua cugcggaac
1933119RNAHepatitis B virus 331cgauccauac ugcggaacu
1933219RNAHepatitis B virus 332cuuuuucacc ucugccuaa
1933319RNAHepatitis B virus 333uuuuucaccu cugccuaau
1933419RNAHepatitis B virus 334uuuucaccuc ugccuaauc
1933519RNAHepatitis B virus 335uuucaccucu gccuaauca
1933619RNAHepatitis B virus 336aagcugugcc uuggguggc
1933719RNAHepatitis B virus 337agcugugccu uggguggcu
1933819RNAHepatitis B virus 338gcugugccuu ggguggcuu
1933919RNAHepatitis B virus 339cugugccuug gguggcuuu
1934019RNAHepatitis B virus 340ggagugugga uucgcacuc
1934119RNAHepatitis B virus 341gaguguggau ucgcacucc
1934219RNAHepatitis B virus 342cagagucuag acucguggu
1934319RNAHepatitis B virus 343auaagaggac ucuuggacu
1934419RNAHepatitis B virus 344uaggaggcug uaggcauaa
1934519RNAHepatitis B virus 345aggaggcugu aggcauaaa
1934619RNAHepatitis B virus 346caugcaacuu uuucaccuc
1934719RNAHepatitis B virus 347augcaacuuu uucaccucu
1934819RNAHepatitis B virus 348uucaccucug ccuaaucau
1934919RNAHepatitis B virus 349ucaccucugc cuaaucauc
1935019RNAHepatitis B virus 350caccucugcc uaaucaucu
1935119RNAHepatitis B virus 351cuccaagcug ugccuuggg
1935219RNAHepatitis B virus 352uccaagcugu gccuugggu
1935319RNAHepatitis B virus 353ccaagcugug ccuugggug
1935419RNAHepatitis B virus 354caagcugugc cuugggugg
1935519RNAHepatitis B virus 355cuagaagaag aacucccuc
1935619RNAHepatitis B virus 356uagaagaaga acucccucg
1935719RNAHepatitis B virus 357agaagaagaa cucccucgc
1935819RNAHepatitis B virus 358guucaagccu ccaagcugu
1935919RNAHepatitis B virus 359agaccaccaa augccccua
1936019RNAHepatitis B virus 360gaccaccaaa ugccccuau
1936119RNAHepatitis B virus 361accaccaaau gccccuauc
1936219RNAHepatitis B virus 362uguauuccca ucccaucau
1936319RNAHepatitis B virus 363guauucccau cccaucauc
1936419RNAHepatitis B virus 364cguagggcuu ucccccacu
1936519RNAHepatitis B virus 365guagggcuuu cccccacug
1936619RNAHepatitis B virus 366uagggcuuuc ccccacugu
1936719RNAHepatitis B virus 367ugccgaucca uacugcgga
1936819RNAHepatitis B virus 368gccgauccau acugcggaa
1936919RNAHepatitis B virus 369cacggggcgc accucucuu
1937019RNAHepatitis B virus 370acggggcgca ccucucuuu
1937119RNAHepatitis B virus 371cggggcgcac cucucuuua
1937219RNAHepatitis B virus 372ggggcgcacc ucucuuuac
1937319RNAHepatitis B virus 373gggcgcaccu cucuuuacg
1937419RNAHepatitis B virus 374ggcgcaccuc ucuuuacgc
1937519RNAHepatitis B virus 375gcgcaccucu cuuuacgcg
1937619RNAHepatitis B virus 376acuguucaag ccuccaagc
1937719RNAHepatitis B virus 377cuguucaagc cuccaagcu
1937819RNAHepatitis B virus 378uguucaagcc uccaagcug
1937919RNAHepatitis B virus 379guauguugcc cguuugucc
1938019RNAHepatitis B virus 380uauguugccc guuuguccu
1938119RNAHepatitis B virus 381uguugcccgu uuguccucu
1938219RNAHepatitis B virus 382ugaaccuuua ccccguugc
1938319RNAHepatitis B virus 383ccauacugcg gaacuccua
1938419RNAHepatitis B virus 384cauacugcgg aacuccuag
1938519RNAHepatitis B virus 385auacugcgga acuccuagc
1938619RNAHepatitis B virus 386ccacggggcg caccucucu
1938719RNAHepatitis B virus 387cccuagaaga agaacuccc
1938819RNAHepatitis B virus 388ccuagaagaa gaacucccu
1938919RNAHepatitis B virus 389ucccucgccu cgcagacga
1939019RNAHepatitis B virus 390uuccucuuca uccugcugc
1939119RNAHepatitis B virus 391uccucuucau ccugcugcu
1939219RNAHepatitis B virus 392ccucuucauc cugcugcua
1939319RNAHepatitis B virus 393cucuucaucc ugcugcuau
1939419RNAHepatitis B virus 394ucuucauccu gcugcuaug
1939519RNAHepatitis B virus 395cuucauccug cugcuaugc
1939619RNAHepatitis B virus 396uucauccugc ugcuaugcc
1939719RNAHepatitis B virus 397ucauccugcu gcuaugccu
1939819RNAHepatitis B virus 398gguauguugc ccguuuguc
1939919RNAHepatitis B virus 399auguugcccg uuuguccuc
1940019RNAHepatitis B virus 400uacgucccgu cggcgcuga
1940119RNAHepatitis B virus 401acgucccguc ggcgcugaa
1940219RNAHepatitis B virus 402cgucccgucg gcgcugaau
1940319RNAHepatitis B virus 403gucccgucgg cgcugaauc
1940419RNAHepatitis B virus 404ucccgucggc gcugaaucc
1940519RNAHepatitis B virus 405aguguggauu cgcacuccu
1940619RNAHepatitis B virus 406ccccuagaag aagaacucc
1940719RNAHepatitis B virus 407caagguaugu ugcccguuu
1940819RNAHepatitis B virus 408aagguauguu gcccguuug
1940919RNAHepatitis B virus 409agguauguug cccguuugu
1941019RNAHepatitis B virus 410ccgaccacgg ggcgcaccu
1941119RNAHepatitis B virus 411cgaccacggg gcgcaccuc
1941219RNAHepatitis B virus 412gaccacgggg cgcaccucu
1941319RNAHepatitis B virus 413accacggggc gcaccucuc
1941419RNAHepatitis B virus 414cuccccgucu gugccuucu
1941519RNAHepatitis B virus 415uccccgucug ugccuucuc
1941619RNAHepatitis B virus 416ccgcgucgca gaagaucuc
1941719RNAHepatitis B virus 417cgcgucgcag aagaucuca
1941819RNAHepatitis B virus 418gcgucgcaga agaucucaa
1941919RNAHepatitis B virus 419cgucgcagaa gaucucaau
1942019RNAHepatitis B virus 420gucgcagaag aucucaauc
1942119RNAHepatitis B virus 421ucgcagaaga ucucaaucu
1942219RNAHepatitis B virus 422aggaccccug cucguguua
1942319RNAHepatitis B virus 423ggaccccugc ucguguuac
1942419RNAHepatitis B virus 424gaccccugcu cguguuaca
1942519RNAHepatitis B virus 425accccugcuc guguuacag
1942619RNAHepatitis B virus 426ccccugcucg uguuacagg
1942719RNAHepatitis B virus 427uaucgcugga ugugucugc
1942819RNAHepatitis B virus 428aucgcuggau gugucugcg
1942919RNAHepatitis B virus 429ucgcuggaug ugucugcgg
1943019RNAHepatitis B virus 430cgcuggaugu gucugcggc
1943119RNAHepatitis B virus 431gcuggaugug ucugcggcg
1943219RNAHepatitis B virus 432cuggaugugu cugcggcgu
1943319RNAHepatitis B virus 433guugcccguu uguccucua
1943419RNAHepatitis B virus 434ccauuuguuc agugguucg
1943519RNAHepatitis B virus 435uuaccaauuu ucuuuuguc
1943619RNAHepatitis B virus 436ccaacuuaca aggccuuuc
1943719RNAHepatitis B virus 437caacuuacaa ggccuuucu
1943819RNAHepatitis B virus 438uuugcugacg caaccccca
1943919RNAHepatitis B virus 439uugcugacgc aacccccac
1944019RNAHepatitis B virus 440ugcugacgca acccccacu
1944119RNAHepatitis B virus 441gcugacgcaa cccccacug
1944219RNAHepatitis B virus 442cugacgcaac ccccacugg
1944319RNAHepatitis B virus 443cugugccuuc ucaucugcc
1944419RNAHepatitis B virus 444ugugccuucu caucugccg
1944519RNAHepatitis B virus 445gugccuucuc aucugccgg
1944619RNAHepatitis B virus 446accagcacca ugcaacuuu
1944719RNAHepatitis B virus 447ccagcaccau gcaacuuuu
1944819RNAHepatitis B virus 448cagcaccaug caacuuuuu
1944919RNAHepatitis B virus 449agcaccaugc aacuuuuuc
1945019RNAHepatitis B virus 450gcaccaugca acuuuuuca
1945119RNAHepatitis B virus 451caccaugcaa cuuuuucac
1945219RNAHepatitis B virus 452accaugcaac uuuuucacc
1945319RNAHepatitis B virus 453ccaugcaacu uuuucaccu
1945419RNAHepatitis B virus 454cgcagaagau cucaaucuc
1945519RNAHepatitis B virus 455uccuaggacc ccugcucgu
1945619RNAHepatitis B virus 456ccuaggaccc cugcucgug
1945719RNAHepatitis B virus 457cuaggacccc ugcucgugu
1945819RNAHepatitis B virus 458uaggaccccu gcucguguu
1945919RNAHepatitis B virus 459cccugcucgu guuacaggc
1946019RNAHepatitis B virus 460ccugcucgug uuacaggcg
1946119RNAHepatitis B virus 461cugcucgugu uacaggcgg
1946219RNAHepatitis B virus 462gccauuuguu cagugguuc
1946319RNAHepatitis B virus 463ucgccaacuu acaaggccu
1946419RNAHepatitis B virus 464cgccaacuua caaggccuu
1946519RNAHepatitis B virus 465gccaacuuac aaggccuuu
1946619RNAHepatitis B virus 466gcgcaugcgu ggaaccuuu
1946719RNAHepatitis B virus 467cugccgaucc auacugcgg
1946819RNAHepatitis B virus 468gcauggagac caccgugaa
1946919RNAHepatitis B virus 469cauggagacc accgugaac
1947019RNAHepatitis B virus 470auggagacca ccgugaacg
1947119RNAHepatitis B virus 471uggagaccac cgugaacgc
1947219RNAHepatitis B virus 472ggagaccacc gugaacgcc
1947319RNAHepatitis B virus 473gagaccaccg ugaacgccc
1947419RNAHepatitis B virus 474caccagcacc augcaacuu
1947519RNAHepatitis B virus 475cccucgccuc gcagacgaa
1947619RNAHepatitis B virus 476ugggguggag cccucaggc
1947719RNAHepatitis B virus 477gccaaaauuc gcagucccc
1947819RNAHepatitis B virus 478ccaaaauucg cagucccca
1947919RNAHepatitis B virus 479caaaauucgc aguccccaa
1948019RNAHepatitis B virus 480uaccaauuuu cuuuugucu
1948119RNAHepatitis B virus 481ugccaagugu uugcugacg
1948219RNAHepatitis B virus 482gccaaguguu ugcugacgc
1948319RNAHepatitis B virus 483ccaaguguuu gcugacgca
1948419RNAHepatitis B virus 484ccucgccucg cagacgaag
1948519RNAHepatitis B virus 485ucucaaucgc cgcgucgca
1948619RNAHepatitis B virus 486cucaaucgcc gcgucgcag
1948719RNAHepatitis B virus 487ucaaucgccg cgucgcaga
1948819RNAHepatitis B virus 488ccuuggacuc auaaggugg
1948919RNAHepatitis B virus 489cuuggacuca uaagguggg
1949019RNAHepatitis B virus 490uccugcuggu ggcuccagu
1949119RNAHepatitis B virus 491uggcucaguu uacuagugc
1949219RNAHepatitis B virus 492uucguagggc uuuccccca
1949319RNAHepatitis B virus 493caaguguuug cugacgcaa
1949419RNAHepatitis B virus 494aaguguuugc ugacgcaac
1949519RNAHepatitis B virus 495aguguuugcu gacgcaacc
1949619RNAHepatitis B virus 496guguuugcug acgcaaccc
1949719RNAHepatitis B virus 497uguuugcuga cgcaacccc
1949819RNAHepatitis B virus 498guuugcugac gcaaccccc
1949919RNAHepatitis B virus 499augucaacga ccgaccuug
1950019RNAHepatitis B virus 500ugucaacgac cgaccuuga
1950119RNAHepatitis B virus 501gucaacgacc gaccuugag
1950219RNAHepatitis B virus 502ucaacgaccg accuugagg
1950319RNAHepatitis B virus 503caacgaccga ccuugaggc
1950419RNAHepatitis B virus 504caaucgccgc gucgcagaa
1950519RNAHepatitis B virus 505aaucgccgcg ucgcagaag
1950619RNAHepatitis B virus 506aucgccgcgu cgcagaaga
1950719RNAHepatitis B virus 507ucgccgcguc gcagaagau
1950819RNAHepatitis B virus 508cgccgcgucg cagaagauc
1950919RNAHepatitis B virus 509gccgcgucgc agaagaucu
1951019RNAHepatitis B virus 510uuccugcugg uggcuccag
1951119RNAHepatitis B virus 511guucguaggg cuuuccccc
1951219RNAHepatitis B virus 512ucguagggcu uucccccac
1951319RNAHepatitis B virus 513cuccucugcc gauccauac
1951419RNAHepatitis B virus 514uccucugccg auccauacu
1951519RNAHepatitis B virus 515ccucugccga uccauacug
1951619RNAHepatitis B virus 516cgcugaaucc cgcggacga
1951719RNAHepatitis B virus 517ccccgucugu gccuucuca
1951819RNAHepatitis B virus 518cccgucugug ccuucucau
1951919RNAHepatitis B virus 519ccgucugugc cuucucauc
1952019RNAHepatitis B virus 520cgucugugcc uucucaucu
1952119RNAHepatitis B virus 521cauaagagga cucuuggac
1952219RNAHepatitis B virus 522gacccuuaua aagaauuug
1952319RNAHepatitis B virus 523guguggauuc gcacuccuc
1952419RNAHepatitis B virus 524gaggcagguc
cccuagaag 1952519RNAHepatitis B virus 525aggcaggucc ccuagaaga
1952619RNAHepatitis B virus 526guccccaacc uccaaucac
1952719RNAHepatitis B virus 527uccccaaccu ccaaucacu
1952819RNAHepatitis B virus 528uaucaaggua uguugcccg
1952919RNAHepatitis B virus 529aucaagguau guugcccgu
1953019RNAHepatitis B virus 530cauuuguuca gugguucgu
1953119RNAHepatitis B virus 531uuuguucagu gguucguag
1953219RNAHepatitis B virus 532uuguucagug guucguagg
1953319RNAHepatitis B virus 533uguucagugg uucguaggg
1953419RNAHepatitis B virus 534guucaguggu ucguagggc
1953519RNAHepatitis B virus 535uucagugguu cguagggcu
1953619RNAHepatitis B virus 536ucagugguuc guagggcuu
1953719RNAHepatitis B virus 537cagugguucg uagggcuuu
1953819RNAHepatitis B virus 538agugguucgu agggcuuuc
1953919RNAHepatitis B virus 539gugguucgua gggcuuucc
1954019RNAHepatitis B virus 540ugguucguag ggcuuuccc
1954119RNAHepatitis B virus 541gguucguagg gcuuucccc
1954219RNAHepatitis B virus 542cagcgcaugc guggaaccu
1954319RNAHepatitis B virus 543agcgcaugcg uggaaccuu
1954419RNAHepatitis B virus 544cgcaugcgug gaaccuuug
1954519RNAHepatitis B virus 545cucugccgau ccauacugc
1954619RNAHepatitis B virus 546ucugccgauc cauacugcg
1954719RNAHepatitis B virus 547gcgcugaauc ccgcggacg
1954819RNAHepatitis B virus 548accucugccu aaucaucuc
1954919RNAHepatitis B virus 549ccgcguaaag agaggugcg
1955019RNAHepatitis B virus 550gagaagucca ccacgaguc
1955119RNAHepatitis B virus 551ugagagaagu ccaccacga
1955219RNAHepatitis B virus 552aacgccgcag acacaucca
1955319RNAHepatitis B virus 553ugaagcgaag ugcacacgg
1955419RNAHepatitis B virus 554ggugaagcga agugcacac
1955519RNAHepatitis B virus 555aggugaagcg aagugcaca
1955619RNAHepatitis B virus 556gaggugaagc gaagugcac
1955719RNAHepatitis B virus 557cagaggugaa gcgaagugc
1955819RNAHepatitis B virus 558cacagcuugg aggcuugaa
1955919RNAHepatitis B virus 559gcacagcuug gaggcuuga
1956019RNAHepatitis B virus 560ggcacagcuu ggaggcuug
1956119RNAHepatitis B virus 561aggcacagcu uggaggcuu
1956219RNAHepatitis B virus 562aguccaccac gagucuaga
1956319RNAHepatitis B virus 563aaguccacca cgagucuag
1956419RNAHepatitis B virus 564gaaguccacc acgagucua
1956519RNAHepatitis B virus 565agaaguccac cacgagucu
1956619RNAHepatitis B virus 566aaaacgccgc agacacauc
1956719RNAHepatitis B virus 567auaaaacgcc gcagacaca
1956819RNAHepatitis B virus 568ugauaaaacg ccgcagaca
1956919RNAHepatitis B virus 569auuuaugccu acagccucc
1957019RNAHepatitis B virus 570aauuuaugcc uacagccuc
1957119RNAHepatitis B virus 571ccaauuuaug ccuacagcc
1957219RNAHepatitis B virus 572accaauuuau gccuacagc
1957319RNAHepatitis B virus 573aggcagaggu gaaaaaguu
1957419RNAHepatitis B virus 574ccaccacgag ucuagacuc
1957519RNAHepatitis B virus 575uccaccacga gucuagacu
1957619RNAHepatitis B virus 576guccaccacg agucuagac
1957719RNAHepatitis B virus 577gaggcauagc agcaggaug
1957819RNAHepatitis B virus 578augaggcaua gcagcagga
1957919RNAHepatitis B virus 579gaugaggcau agcagcagg
1958019RNAHepatitis B virus 580agaugaggca uagcagcag
1958119RNAHepatitis B virus 581aagaugaggc auagcagca
1958219RNAHepatitis B virus 582gaccaauuua ugccuacag
1958319RNAHepatitis B virus 583agaccaauuu augccuaca
1958419RNAHepatitis B virus 584agagaagucc accacgagu
1958519RNAHepatitis B virus 585gagagaaguc caccacgag
1958619RNAHepatitis B virus 586gugaagcgaa gugcacacg
1958719RNAHepatitis B virus 587agaggugaag cgaagugca
1958819RNAHepatitis B virus 588gcagagguga agcgaagug
1958919RNAHepatitis B virus 589ugcagaggug aagcgaagu
1959019RNAHepatitis B virus 590aaggcacagc uuggaggcu
1959119RNAHepatitis B virus 591caaggcacag cuuggaggc
1959219RNAHepatitis B virus 592cugcgaggcg agggaguuc
1959319RNAHepatitis B virus 593ucugcgaggc gagggaguu
1959419RNAHepatitis B virus 594gucugcgagg cgagggagu
1959519RNAHepatitis B virus 595cgucugcgag gcgagggag
1959619RNAHepatitis B virus 596aacuggagcc accagcagg
1959719RNAHepatitis B virus 597gaacuggagc caccagcag
1959819RNAHepatitis B virus 598aaacgccgca gacacaucc
1959919RNAHepatitis B virus 599uaaaacgccg cagacacau
1960019RNAHepatitis B virus 600gauaaaacgc cgcagacac
1960119RNAHepatitis B virus 601augauaaaac gccgcagac
1960219RNAHepatitis B virus 602ugaggcccac ucccauagg
1960319RNAHepatitis B virus 603cugaggccca cucccauag
1960419RNAHepatitis B virus 604gugcagaggu gaagcgaag
1960519RNAHepatitis B virus 605cgugcagagg ugaagcgaa
1960619RNAHepatitis B virus 606acgugcagag gugaagcga
1960719RNAHepatitis B virus 607caauuuaugc cuacagccu
1960819RNAHepatitis B virus 608uaggcagagg ugaaaaagu
1960919RNAHepatitis B virus 609ugaggcauag cagcaggau
1961019RNAHepatitis B virus 610gaagaugagg cauagcagc
1961119RNAHepatitis B virus 611agaagaugag gcauagcag
1961219RNAHepatitis B virus 612aagaagauga ggcauagca
1961319RNAHepatitis B virus 613cagaccaauu uaugccuac
1961419RNAHepatitis B virus 614ccaaggcaca gcuuggagg
1961519RNAHepatitis B virus 615uugagagaag uccaccacg
1961619RNAHepatitis B virus 616auugagagaa guccaccac
1961719RNAHepatitis B virus 617aauugagaga aguccacca
1961819RNAHepatitis B virus 618aaauugagag aaguccacc
1961919RNAHepatitis B virus 619aaaauugaga gaaguccac
1962019RNAHepatitis B virus 620gaaaauugag agaagucca
1962119RNAHepatitis B virus 621uagaaaauug agagaaguc
1962219RNAHepatitis B virus 622cuagaaaauu gagagaagu
1962319RNAHepatitis B virus 623ccuagaaaau ugagagaag
1962419RNAHepatitis B virus 624cccuagaaaa uugagagaa
1962519RNAHepatitis B virus 625ccccuagaaa auugagaga
1962619RNAHepatitis B virus 626ggaguuccgc aguauggau
1962719RNAHepatitis B virus 627aggaguuccg caguaugga
1962819RNAHepatitis B virus 628ggcgagggag uucuucuuc
1962919RNAHepatitis B virus 629aggcgaggga guucuucuu
1963019RNAHepatitis B virus 630gaggcgaggg aguucuucu
1963119RNAHepatitis B virus 631cgaggcgagg gaguucuuc
1963219RNAHepatitis B virus 632gcgaggcgag ggaguucuu
1963319RNAHepatitis B virus 633ugcgaggcga gggaguucu
1963419RNAHepatitis B virus 634caccacgagu cuagacucu
1963519RNAHepatitis B virus 635agaaaauuga gagaagucc
1963619RNAHepatitis B virus 636gaguuccgca guauggauc
1963719RNAHepatitis B virus 637cagaggugaa aaaguugca
1963819RNAHepatitis B virus 638gcagagguga aaaaguugc
1963919RNAHepatitis B virus 639ggcagaggug aaaaaguug
1964019RNAHepatitis B virus 640ggacugcgaa uuuuggcca
1964119RNAHepatitis B virus 641gggacugcga auuuuggcc
1964219RNAHepatitis B virus 642guuccgcagu auggaucgg
1964319RNAHepatitis B virus 643aguuccgcag uauggaucg
1964419RNAHepatitis B virus 644uuaggcagag gugaaaaag
1964519RNAHepatitis B virus 645auuaggcaga ggugaaaaa
1964619RNAHepatitis B virus 646gauuaggcag aggugaaaa
1964719RNAHepatitis B virus 647ugauuaggca gaggugaaa
1964819RNAHepatitis B virus 648gccacccaag gcacagcuu
1964919RNAHepatitis B virus 649agccacccaa ggcacagcu
1965019RNAHepatitis B virus 650aagccaccca aggcacagc
1965119RNAHepatitis B virus 651aaagccaccc aaggcacag
1965219RNAHepatitis B virus 652gagugcgaau ccacacucc
1965319RNAHepatitis B virus 653ggagugcgaa uccacacuc
1965419RNAHepatitis B virus 654accacgaguc uagacucug
1965519RNAHepatitis B virus 655aguccaagag uccucuuau
1965619RNAHepatitis B virus 656uuaugccuac agccuccua
1965719RNAHepatitis B virus 657uuuaugccua cagccuccu
1965819RNAHepatitis B virus 658gaggugaaaa aguugcaug
1965919RNAHepatitis B virus 659agaggugaaa aaguugcau
1966019RNAHepatitis B virus 660augauuaggc agaggugaa
1966119RNAHepatitis B virus 661gaugauuagg cagagguga
1966219RNAHepatitis B virus 662agaugauuag gcagaggug
1966319RNAHepatitis B virus 663cccaaggcac agcuuggag
1966419RNAHepatitis B virus 664acccaaggca cagcuugga
1966519RNAHepatitis B virus 665cacccaaggc acagcuugg
1966619RNAHepatitis B virus 666ccacccaagg cacagcuug
1966719RNAHepatitis B virus 667gagggaguuc uucuucuag
1966819RNAHepatitis B virus 668cgagggaguu cuucuucua
1966919RNAHepatitis B virus 669gcgagggagu ucuucuucu
1967019RNAHepatitis B virus 670acagcuugga ggcuugaac
1967119RNAHepatitis B virus 671uaggggcauu ugguggucu
1967219RNAHepatitis B virus 672auaggggcau uuggugguc
1967319RNAHepatitis B virus 673gauaggggca uuugguggu
1967419RNAHepatitis B virus 674augaugggau gggaauaca
1967519RNAHepatitis B virus 675gaugauggga ugggaauac
1967619RNAHepatitis B virus 676agugggggaa agcccuacg
1967719RNAHepatitis B virus 677caguggggga aagcccuac
1967819RNAHepatitis B virus 678acaguggggg aaagcccua
1967919RNAHepatitis B virus 679uccgcaguau ggaucggca
1968019RNAHepatitis B virus 680uuccgcagua uggaucggc
1968119RNAHepatitis B virus 681aagagaggug cgccccgug
1968219RNAHepatitis B virus 682aaagagaggu gcgccccgu
1968319RNAHepatitis B virus 683uaaagagagg ugcgccccg
1968419RNAHepatitis B virus 684guaaagagag gugcgcccc
1968519RNAHepatitis B virus 685cguaaagaga ggugcgccc
1968619RNAHepatitis B virus 686gcguaaagag aggugcgcc
1968719RNAHepatitis B virus 687cgcguaaaga gaggugcgc
1968819RNAHepatitis B virus 688gcuuggaggc uugaacagu
1968919RNAHepatitis B virus 689agcuuggagg cuugaacag
1969019RNAHepatitis B virus 690cagcuuggag gcuugaaca
1969119RNAHepatitis B virus 691ggacaaacgg gcaacauac
1969219RNAHepatitis B virus 692aggacaaacg ggcaacaua
1969319RNAHepatitis B virus 693agaggacaaa cgggcaaca
1969419RNAHepatitis B virus 694gcaacggggu aaagguuca
1969519RNAHepatitis B virus 695uaggaguucc gcaguaugg
1969619RNAHepatitis B virus 696cuaggaguuc cgcaguaug
1969719RNAHepatitis B virus 697gcuaggaguu ccgcaguau
1969819RNAHepatitis B virus 698agagaggugc gccccgugg
1969919RNAHepatitis B virus 699gggaguucuu cuucuaggg
1970019RNAHepatitis B virus 700agggaguucu ucuucuagg
1970119RNAHepatitis B virus 701ucgucugcga ggcgaggga
1970219RNAHepatitis B virus 702gcagcaggau gaagaggaa
1970319RNAHepatitis B virus 703agcagcagga ugaagagga
1970419RNAHepatitis B virus 704uagcagcagg augaagagg
1970519RNAHepatitis B virus 705auagcagcag gaugaagag
1970619RNAHepatitis B virus 706cauagcagca ggaugaaga
1970719RNAHepatitis B virus 707gcauagcagc aggaugaag
1970819RNAHepatitis B virus 708ggcauagcag caggaugaa
1970919RNAHepatitis B virus 709aggcauagca gcaggauga
1971019RNAHepatitis B virus 710gacaaacggg caacauacc
1971119RNAHepatitis B virus 711gaggacaaac gggcaacau
1971219RNAHepatitis B virus 712ucagcgccga cgggacgua
1971319RNAHepatitis B virus 713uucagcgccg acgggacgu
1971419RNAHepatitis B virus 714auucagcgcc gacgggacg
1971519RNAHepatitis B virus 715gauucagcgc cgacgggac
1971619RNAHepatitis B virus 716ggauucagcg ccgacggga
1971719RNAHepatitis B virus 717aggagugcga auccacacu
1971819RNAHepatitis B virus 718ggaguucuuc uucuagggg
1971919RNAHepatitis B virus 719aaacgggcaa cauaccuug
1972019RNAHepatitis B virus 720caaacgggca acauaccuu
1972119RNAHepatitis B virus 721acaaacgggc aacauaccu
1972219RNAHepatitis B virus 722aggugcgccc cguggucgg
1972319RNAHepatitis B virus 723gaggugcgcc ccguggucg
1972419RNAHepatitis B virus 724agaggugcgc cccgugguc
1972519RNAHepatitis B virus 725gagaggugcg ccccguggu
1972619RNAHepatitis B virus 726agaaggcaca gacggggag
1972719RNAHepatitis B virus 727gagaaggcac agacgggga
1972819RNAHepatitis B virus 728gagaucuucu gcgacgcgg
1972919RNAHepatitis B virus 729ugagaucuuc ugcgacgcg
1973019RNAHepatitis B virus 730uugagaucuu cugcgacgc
1973119RNAHepatitis B virus 731auugagaucu ucugcgacg
1973219RNAHepatitis B virus 732gauugagauc uucugcgac
1973319RNAHepatitis B virus 733agauugagau cuucugcga
1973419RNAHepatitis B virus 734uaacacgagc agggguccu
1973519RNAHepatitis B virus 735guaacacgag caggggucc
1973619RNAHepatitis B virus 736uguaacacga gcagggguc
1973719RNAHepatitis B virus 737cuguaacacg agcaggggu
1973819RNAHepatitis B virus 738ccuguaacac gagcagggg
1973919RNAHepatitis B virus 739gcagacacau ccagcgaua
1974019RNAHepatitis B virus 740cgcagacaca uccagcgau
1974119RNAHepatitis B virus 741ccgcagacac auccagcga
1974219RNAHepatitis B virus 742gccgcagaca cauccagcg
1974319RNAHepatitis B virus 743cgccgcagac acauccagc
1974419RNAHepatitis B virus 744acgccgcaga cacauccag
1974519RNAHepatitis B virus 745uagaggacaa acgggcaac
1974619RNAHepatitis B virus 746cgaaccacug aacaaaugg
1974719RNAHepatitis B virus 747gacaaaagaa aauugguaa
1974819RNAHepatitis B virus 748gaaaggccuu guaaguugg
1974919RNAHepatitis B virus 749agaaaggccu uguaaguug
1975019RNAHepatitis B virus 750uggggguugc gucagcaaa
1975119RNAHepatitis B virus 751guggggguug cgucagcaa
1975219RNAHepatitis B virus 752aguggggguu gcgucagca
1975319RNAHepatitis B virus 753cagugggggu ugcgucagc
1975419RNAHepatitis B virus 754ccaguggggg uugcgucag
1975519RNAHepatitis B virus 755ggcagaugag aaggcacag
1975619RNAHepatitis B virus 756cggcagauga gaaggcaca
1975719RNAHepatitis B virus 757ccggcagaug agaaggcac
1975819RNAHepatitis B virus 758aaaguugcau ggugcuggu
1975919RNAHepatitis B virus 759aaaaguugca uggugcugg
1976019RNAHepatitis B virus 760aaaaaguugc auggugcug
1976119RNAHepatitis B virus 761gaaaaaguug cauggugcu
1976219RNAHepatitis B virus 762ugaaaaaguu gcauggugc
1976319RNAHepatitis B virus 763gugaaaaagu ugcauggug
1976419RNAHepatitis B virus 764ggugaaaaag uugcauggu
1976519RNAHepatitis B virus 765aggugaaaaa guugcaugg
1976619RNAHepatitis B virus 766gagauugaga ucuucugcg
1976719RNAHepatitis B virus 767acgagcaggg guccuagga
1976819RNAHepatitis B virus 768cacgagcagg gguccuagg
1976919RNAHepatitis B virus 769acacgagcag ggguccuag
1977019RNAHepatitis B virus 770aacacgagca gggguccua
1977119RNAHepatitis B virus 771gccuguaaca cgagcaggg
1977219RNAHepatitis B virus 772cgccuguaac acgagcagg
1977319RNAHepatitis B virus 773ccgccuguaa cacgagcag
1977419RNAHepatitis B virus 774gaaccacuga acaaauggc
1977519RNAHepatitis B virus 775aggccuugua aguuggcga
1977619RNAHepatitis B virus 776aaggccuugu aaguuggcg
1977719RNAHepatitis B virus 777aaaggccuug uaaguuggc
1977819RNAHepatitis B virus 778aaagguucca cgcaugcgc
1977919RNAHepatitis B virus 779ccgcaguaug gaucggcag
1978019RNAHepatitis B virus 780uucacggugg ucuccaugc
1978119RNAHepatitis B virus 781guucacggug gucuccaug
1978219RNAHepatitis B virus 782cguucacggu ggucuccau
1978319RNAHepatitis B virus 783gcguucacgg uggucucca
1978419RNAHepatitis B virus 784ggcguucacg guggucucc
1978519RNAHepatitis B virus 785gggcguucac gguggucuc
1978619RNAHepatitis B virus 786aaguugcaug gugcuggug
1978719RNAHepatitis B virus 787uucgucugcg aggcgaggg
1978819RNAHepatitis B virus 788gccugagggc uccacccca
1978919RNAHepatitis B virus 789ggggacugcg aauuuuggc
1979019RNAHepatitis B virus 790uggggacugc gaauuuugg
1979119RNAHepatitis B virus 791uuggggacug cgaauuuug
1979219RNAHepatitis B virus 792agacaaaaga aaauuggua
1979319RNAHepatitis B virus 793cgucagcaaa cacuuggca
1979419RNAHepatitis B virus 794gcgucagcaa acacuuggc
1979519RNAHepatitis B virus 795ugcgucagca aacacuugg
1979619RNAHepatitis B virus 796cuucgucugc gaggcgagg
1979719RNAHepatitis B virus 797ugcgacgcgg cgauugaga
1979819RNAHepatitis B virus 798cugcgacgcg gcgauugag
1979919RNAHepatitis B virus 799ucugcgacgc ggcgauuga
1980019RNAHepatitis B virus 800ccaccuuaug aguccaagg
1980119RNAHepatitis B virus 801cccaccuuau gaguccaag
1980219RNAHepatitis B virus 802acuggagcca ccagcagga
1980319RNAHepatitis B virus 803gcacuaguaa acugagcca
1980419RNAHepatitis B virus 804ugggggaaag cccuacgaa
1980519RNAHepatitis B virus 805uugcgucagc aaacacuug
1980619RNAHepatitis B virus 806guugcgucag caaacacuu
1980719RNAHepatitis B virus 807gguugcguca gcaaacacu
1980819RNAHepatitis B virus 808ggguugcguc agcaaacac
1980919RNAHepatitis B virus 809gggguugcgu cagcaaaca
1981019RNAHepatitis B virus 810ggggguugcg ucagcaaac
1981119RNAHepatitis B virus 811caaggucggu cguugacau
1981219RNAHepatitis B virus 812ucaaggucgg ucguugaca
1981319RNAHepatitis B virus 813cucaaggucg gucguugac
1981419RNAHepatitis B virus 814ccucaagguc ggucguuga
1981519RNAHepatitis B virus 815gccucaaggu cggucguug
1981619RNAHepatitis B virus 816uucugcgacg cggcgauug
1981719RNAHepatitis B virus 817cuucugcgac gcggcgauu
1981819RNAHepatitis B virus 818ucuucugcga cgcggcgau
1981919RNAHepatitis B virus 819aucuucugcg acgcggcga
1982019RNAHepatitis B virus 820gaucuucugc gacgcggcg
1982119RNAHepatitis B virus 821agaucuucug cgacgcggc
1982219RNAHepatitis B virus 822cuggagccac cagcaggaa
1982319RNAHepatitis B virus 823gggggaaagc ccuacgaac
1982419RNAHepatitis B virus 824gugggggaaa gcccuacga
1982519RNAHepatitis B virus 825guauggaucg gcagaggag
1982619RNAHepatitis B virus 826aguauggauc ggcagagga
1982719RNAHepatitis B virus 827caguauggau cggcagagg
1982819RNAHepatitis B virus 828ucguccgcgg gauucagcg
1982919RNAHepatitis B virus 829ugagaaggca cagacgggg
1983019RNAHepatitis B virus 830augagaaggc acagacggg
1983119RNAHepatitis B virus 831gaugagaagg cacagacgg
1983219RNAHepatitis B virus 832agaugagaag gcacagacg
1983319RNAHepatitis B virus 833guccaagagu ccucuuaug
1983419RNAHepatitis B virus 834caaauucuuu auaaggguc
1983519RNAHepatitis B virus 835gaggagugcg aauccacac
1983619RNAHepatitis B virus 836cuucuagggg accugccuc
1983719RNAHepatitis B virus 837ucuucuaggg gaccugccu
1983819RNAHepatitis B virus 838gugauuggag guuggggac
1983919RNAHepatitis B virus 839agugauugga gguugggga
1984019RNAHepatitis B virus 840cgggcaacau accuugaua
1984119RNAHepatitis B virus 841acgggcaaca uaccuugau
1984219RNAHepatitis B virus 842acgaaccacu gaacaaaug
1984319RNAHepatitis B virus 843cuacgaacca cugaacaaa
1984419RNAHepatitis B virus 844ccuacgaacc acugaacaa
1984519RNAHepatitis B virus 845cccuacgaac cacugaaca
1984619RNAHepatitis B virus 846gcccuacgaa ccacugaac
1984719RNAHepatitis B virus 847agcccuacga accacugaa
1984819RNAHepatitis B virus 848aagcccuacg aaccacuga
1984919RNAHepatitis B virus 849aaagcccuac gaaccacug
1985019RNAHepatitis B virus 850gaaagcccua cgaaccacu
1985119RNAHepatitis B virus 851ggaaagcccu acgaaccac
1985219RNAHepatitis B virus 852gggaaagccc uacgaacca
1985319RNAHepatitis B virus 853ggggaaagcc cuacgaacc
1985419RNAHepatitis B virus 854agguuccacg caugcgcug
1985519RNAHepatitis B virus 855aagguuccac gcaugcgcu
1985619RNAHepatitis B virus 856caaagguucc acgcaugcg
1985719RNAHepatitis B virus 857gcaguaugga ucggcagag
1985819RNAHepatitis B virus 858cgcaguaugg aucggcaga
1985919RNAHepatitis B virus 859cguccgcggg auucagcgc
1986019RNAHepatitis B virus 860gagaugauua ggcagaggu
1986119RNAHepatitis B virus 861cgcaccucuc uuuacgcgg
1986219RNAHepatitis B virus 862gacucguggu ggacuucuc
1986319RNAHepatitis B virus 863ucguggugga cuucucuca
1986419RNAHepatitis B virus 864uggauguguc ugcggcguu
1986519RNAHepatitis B virus 865ccgugugcac uucgcuuca
1986619RNAHepatitis B virus 866gugugcacuu cgcuucacc
1986719RNAHepatitis B virus 867ugugcacuuc gcuucaccu
1986819RNAHepatitis B virus 868gugcacuucg cuucaccuc
1986919RNAHepatitis B virus 869gcacuucgcu ucaccucug
1987019RNAHepatitis B virus 870ucuagacucg ugguggacu
1987119RNAHepatitis B virus 871cuagacucgu gguggacuu
1987219RNAHepatitis B virus 872uagacucgug guggacuuc
1987319RNAHepatitis B virus 873agacucgugg uggacuucu
1987419RNAHepatitis B virus 874ggaggcugua ggcauaaau
1987519RNAHepatitis B virus 875gaggcuguag gcauaaauu
1987619RNAHepatitis B virus 876ggcuguaggc auaaauugg
1987719RNAHepatitis B virus 877gcuguaggca uaaauuggu
1987819RNAHepatitis B virus 878cuguaggcau aaauugguc
1987919RNAHepatitis B virus 879uguaggcaua aauuggucu
1988019RNAHepatitis B virus 880gugguggacu ucucucaau
1988119RNAHepatitis B virus 881uucaagccuc caagcugug
1988219RNAHepatitis B virus 882ucaagccucc aagcugugc
1988319RNAHepatitis B virus 883caagccucca agcugugcc
1988419RNAHepatitis B virus 884aagccuccaa gcugugccu
1988519RNAHepatitis B virus 885gaugugucug cggcguuuu
1988619RNAHepatitis B virus 886ugugucugcg gcguuuuau
1988719RNAHepatitis B virus 887ugucugcggc guuuuauca
1988819RNAHepatitis B virus 888aacuuuuuca ccucugccu
1988919RNAHepatitis B virus 889gagucuagac ucguggugg
1989019RNAHepatitis B virus 890agucuagacu cguggugga
1989119RNAHepatitis B virus 891gucuagacuc gugguggac
1989219RNAHepatitis B virus 892cauccugcug cuaugccuc
1989319RNAHepatitis B virus 893uccugcugcu augccucau
1989419RNAHepatitis B virus 894ccugcugcua ugccucauc
1989519RNAHepatitis B virus 895cugcugcuau gccucaucu
1989619RNAHepatitis B virus 896ugcugcuaug ccucaucuu
1989719RNAHepatitis B virus 897acucguggug gacuucucu
1989819RNAHepatitis B virus 898cucguggugg acuucucuc
1989919RNAHepatitis B virus 899cgugugcacu ucgcuucac
1990019RNAHepatitis B virus 900ugcacuucgc uucaccucu
1990119RNAHepatitis B virus 901cacuucgcuu caccucugc
1990219RNAHepatitis B virus 902ccgcguaaag agaggugcg
1990319RNAHepatitis B virus 903gagaagucca ccacgaguc
1990419RNAHepatitis B virus 904ugagagaagu ccaccacga
1990519RNAHepatitis B virus 905aacgccgcag acacaucca
1990619RNAHepatitis B virus 906ugaagcgaag ugcacacgg
1990719RNAHepatitis B virus 907ggugaagcga agugcacac
1990819RNAHepatitis B virus 908aggugaagcg aagugcaca
1990919RNAHepatitis B virus 909gaggugaagc gaagugcac
1991019RNAHepatitis B virus 910cagaggugaa gcgaagugc
1991119RNAHepatitis B virus 911aguccaccac gagucuaga
1991219RNAHepatitis B virus 912aaguccacca cgagucuag
1991319RNAHepatitis B virus 913gaaguccacc acgagucua
1991419RNAHepatitis B virus 914agaaguccac cacgagucu
1991519RNAHepatitis B virus 915auuuaugccu acagccucc
1991619RNAHepatitis B virus 916aauuuaugcc uacagccuc
1991719RNAHepatitis B virus 917ccaauuuaug ccuacagcc
1991819RNAHepatitis B virus 918accaauuuau gccuacagc
1991919RNAHepatitis B virus 919gaccaauuua ugccuacag
1992019RNAHepatitis B virus 920agaccaauuu augccuaca
1992119RNAHepatitis B virus 921auugagagaa guccaccac
1992219RNAHepatitis B virus 922cacagcuugg aggcuugaa
1992319RNAHepatitis B virus 923gcacagcuug gaggcuuga
1992419RNAHepatitis B virus 924ggcacagcuu ggaggcuug
1992519RNAHepatitis B virus 925aggcacagcu uggaggcuu
1992619RNAHepatitis B virus 926aaaacgccgc agacacauc
1992719RNAHepatitis B virus 927auaaaacgcc gcagacaca
1992819RNAHepatitis B virus 928ugauaaaacg ccgcagaca
1992919RNAHepatitis B virus 929aggcagaggu gaaaaaguu
1993019RNAHepatitis B virus 930ccaccacgag ucuagacuc
1993119RNAHepatitis B virus 931uccaccacga gucuagacu
1993219RNAHepatitis B virus 932guccaccacg agucuagac
1993319RNAHepatitis B virus 933gaggcauagc agcaggaug
1993419RNAHepatitis B virus 934augaggcaua gcagcagga
1993519RNAHepatitis B virus 935gaugaggcau agcagcagg
1993619RNAHepatitis B virus 936agaugaggca uagcagcag
1993719RNAHepatitis B virus 937aagaugaggc auagcagca
1993819RNAHepatitis B virus 938agagaagucc accacgagu
1993919RNAHepatitis B virus 939gagagaaguc caccacgag
1994019RNAHepatitis B virus 940gugaagcgaa gugcacacg
1994119RNAHepatitis B virus 941agaggugaag cgaagugca
1994219RNAHepatitis B virus 942gcagagguga agcgaagug
1994321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 943gagucuagac ucgugguggu u
2194421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 944ccaccacgag ucuagacucu u
2194521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 945agucuagacu cgugguggau u
2194621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 946uccaccacga gucuagacuu u
2194721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 947gucuagacuc gugguggacu u
2194821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 948guccaccacg agucuagacu u
2194921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 949ucuagacucg ugguggacuu u
2195021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 950aguccaccac gagucuagau u
2195121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 951cuagacucgu gguggacuuu u
2195221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 952aaguccacca cgagucuagu u
2195321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 953uagacucgug guggacuucu u
2195421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 954gaaguccacc acgagucuau u
2195521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 955agacucgugg uggacuucuu u
2195621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 956agaaguccac cacgagucuu u
2195721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 957gacucguggu ggacuucucu u
2195821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 958gagaagucca ccacgagucu u
2195921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 959acucguggug gacuucucuu u
2196021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 960agagaagucc accacgaguu u
2196121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 961cucguggugg acuucucucu u
2196221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 962gagagaaguc caccacgagu u
2196321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 963ucguggugga cuucucucau u
2196421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 964ugagagaagu ccaccacgau u
2196521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 965gugguggacu ucucucaauu u
2196621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 966auugagagaa guccaccacu u
2196721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 967uggauguguc ugcggcguuu u
2196821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 968aacgccgcag acacauccau u
2196921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 969gaugugucug cggcguuuuu u
2197021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 970aaaacgccgc agacacaucu u
2197121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 971ugugucugcg gcguuuuauu u
2197221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 972auaaaacgcc gcagacacau u
2197321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 973ugucugcggc guuuuaucau u
2197421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 974ugauaaaacg ccgcagacau u
2197521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 975cauccugcug cuaugccucu u
2197621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 976gaggcauagc agcaggaugu u
2197721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 977uccugcugcu augccucauu u
2197821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 978augaggcaua gcagcaggau u
2197921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 979ccugcugcua ugccucaucu u
2198021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 980gaugaggcau agcagcaggu u
2198121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 981cugcugcuau gccucaucuu u
2198221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 982agaugaggca uagcagcagu u
2198321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 983ugcugcuaug ccucaucuuu u
2198421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 984aagaugaggc auagcagcau u
2198521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 985cgcaccucuc uuuacgcggu u
2198621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 986ccgcguaaag agaggugcgu u
2198721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 987ccgugugcac uucgcuucau u
2198821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 988ugaagcgaag ugcacacggu u
2198921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 989cgugugcacu ucgcuucacu u
2199021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 990gugaagcgaa gugcacacgu u
2199121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 991gugugcacuu cgcuucaccu u
2199221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 992ggugaagcga agugcacacu u
2199321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 993ugugcacuuc gcuucaccuu u
2199421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 994aggugaagcg aagugcacau u
2199521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 995gugcacuucg cuucaccucu u
2199621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 996gaggugaagc gaagugcacu u
2199721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 997ugcacuucgc uucaccucuu u
2199821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 998agaggugaag cgaagugcau u
2199921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 999gcacuucgcu ucaccucugu u
21100021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1000cagaggugaa gcgaagugcu u
21100121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1001cacuucgcuu caccucugcu u
21100221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1002gcagagguga agcgaagugu u
21100321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1003ggaggcugua ggcauaaauu u
21100421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1004auuuaugccu acagccuccu u
21100521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1005gaggcuguag gcauaaauuu u
21100621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1006aauuuaugcc uacagccucu u
21100721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1007ggcuguaggc auaaauuggu u
21100821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1008ccaauuuaug ccuacagccu u
21100921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1009gcuguaggca uaaauugguu u
21101021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1010accaauuuau gccuacagcu u
21101121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1011cuguaggcau aaauuggucu u
21101221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1012gaccaauuua ugccuacagu u
21101321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1013uguaggcaua aauuggucuu u
21101421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1014agaccaauuu augccuacau u
21101521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1015aacuuuuuca ccucugccuu u
21101621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1016aggcagaggu gaaaaaguuu u
21101721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1017uucaagccuc caagcugugu u
21101821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1018cacagcuugg aggcuugaau u
21101921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1019ucaagccucc aagcugugcu u
21102021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1020gcacagcuug gaggcuugau u
21102121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1021caagccucca agcugugccu u
21102221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1022ggcacagcuu ggaggcuugu u
21102321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1023aagccuccaa gcugugccuu u
21102421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1024aggcacagcu uggaggcuuu u
21102521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1025cgugugcacu ucgcuucacu u
21102621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1026gugaagcgaa gugcacacgu u
21102721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1027cgugugcacu ucgcuucacu u
21102821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1028gugaagcgaa gugcacacgu u
21102921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1029cgugugcacu ucgcuucacu u
21103021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1030gugaagcgaa gugcacacgu u
21103121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1031cgugugcacu ucgcuucacu u
21103221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1032gugaagcgaa gugcacacgu u
21103321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1033cgugugcacu ucgcuucacu u
21103421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1034gugaagcgaa gugcacacgu u
21103521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1035cgugugcacu ucgcuucacu u
21103621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1036gugaagcgaa gugcacacgu u
21103721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1037cgugugcacu ucgcuucacu u
21103821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1038gugaagcgaa gugcacacgu u
21103921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1039cgugugcacu ucgcuucacu u
21104021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1040gugaagcgaa gugcacacgu u
21104121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1041ccgugugcac uucgcuucau u
21104221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1042ugaagcgaag ugcacacggu u
21104321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1043ccgugugcac uucgcuucau u
21104421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1044ugaagcgaag ugcacacggu u
21104521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1045ccgugugcac uucgcuucau u
21104621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1046ugaagcgaag ugcacacggu u
21104721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1047ugugcacuuc gcuucaccuu u
21104821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1048aggugaagcg aagugcacau u
21104921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1049ugugcacuuc gcuucaccuu u
21105021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1050aggugaagcg aagugcacau u
21105121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1051ugugcacuuc gcuucaccuu u
21105221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1052aggugaagcg aagugcacau u
21105321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1053aacuuuuuca ccucugccuu u
21105421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1054aggcagaggu gaaaaaguuu u
21105521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1055aacuuuuuca ccucugccuu u
21105621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1056aggcagaggu gaaaaaguuu u
21105721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1057aacuuuuuca ccucugccuu u
21105821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1058aggcagaggu gaaaaaguuu u
21105921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1059agucuagacu cgugguggau u
21106021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1060uccaccacga gucuagacuu u
21106121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1061ugcacuucgc uucaccucuu u
21106221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1062agaggugaag cgaagugcau u
21106321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1063ugcacuucgc uucaccucuu u
21106421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1064agaggugaag cgaagugcau u
21106521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1065ugcacuucgc uucaccucuu u
21106621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1066agaggugaag cgaagugcau u
21106721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1067ugcacuucgc uucaccucuu u
21106821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1068agaggugaag cgaagugcau u
21106921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1069ugugcacuuc gcuucaccuu u
21107021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1070aggugaagcg aagugcacau u
21107121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1071ugugcacuuc gcuucaccuu u
21107221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1072aggugaagcg aagugcacau u
21107321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1073ugugcacuuc gcuucaccuu u
21107421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1074aggugaagcg aagugcacau u
21107521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1075ugugcacuuc gcuucaccuu u
21107621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1076aggugaagcg aagugcacau u
21107721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1077ugugcacuuc gcuucaccuu u
21107821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1078aggugaagcg aagugcacau u
21107921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1079ugugcacuuc gcuucaccuu u
21108021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1080aggugaagcg aagugcacau u
21108121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1081ugugcacuuc gcuucaccuu u
21108221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1082aggugaagcg aagugcacau u
21108321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1083ugugcacuuc gcuucaccuu u
21108421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1084aggugaagcg aagugcacau u
21108521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1085ugugcacuuc gcuucaccuu u
21108621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1086aggugaagcg aagugcacau u
21108721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1087ugugcacuuc gcuucaccuu u
21108821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1088aggugaagcg aagugcacau u
21108921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1089ugugcacuuc gcuucaccuu u
21109021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1090aggugaagcg aagugcacau u
21109121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1091ugugcacuuc gcuucaccuu u
21109221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1092aggugaagcg aagugcacau u
21109321RNAArtificial SequenceDescription of Artificial
Sequence
Synthetic oligonucleotide 1093ugugcacuuc gcuucaccuu u
21109421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1094aggugaagcg aagugcacau u
21109521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1095ugugcacuuc gcuucaccuu u
21109621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1096aggugaagcg aagugcacau u
21109721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1097ugugcacuuc gcuucaccuu u
21109821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1098aggugaagcg aagugcacau u
21109921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1099ugugcacuuc gcuucaccuu u
21110021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1100aggugaagcg aagugcacau u
21110121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1101gaggcuguag gcauaaauuu u
21110221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1102aauuuaugcc uacagccucu u
21110321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1103gaggcuguag gcauaaauuu u
21110421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1104aauuuaugcc uacagccucu u
21110521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1105gaggcuguag gcauaaauuu u
21110621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1106aauuuaugcc uacagccucu u
21110721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1107ugucugcggc guuuuaucau u
21110821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1108ugauaaaacg ccgcagacau u
21110921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1109ugucugcggc guuuuaucau u
21111021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1110ugauaaaacg ccgcagacau u
21111121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1111ugucugcggc guuuuaucau u
21111221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1112ugauaaaacg ccgcagacau u
21111321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1113ugucugcggc guuuuaucau u
21111421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1114ugauaaaacg ccgcagacau u
21111521RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1115cgugugcacu ucgcuucacu u
21111621RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1116gugaagcgaa gugcacacgu u
21111721RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1117ccgugugcac uucgcuucau u
21111821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1118ugaagcgaag ugcacacggu u
21111921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1119ugcacuucgc uucaccucuu u
21112021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1120agaggugaag cgaagugcau u
21112121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1121ugugcacuuc gcuucaccuu t
21112221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1122aggugaagcg aagugcacau t
21112321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1123ugugcacuuc gcuucaccuu t
21112421DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1124aggugaagcg aagugcacau t
21112521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1125ugugcacuuc gcuucaccuu t
21112621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1126aggugaagcg aagugcacau t
21112721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1127ugugcacuuc gcuucaccuu t
21112821DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1128aggugaagcg aagugcacau t
21112921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1129gaggcuguag gcauaaauuu t
21113021DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1130gaggcuguag gcauaaauuu t
21113121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1131gaggcuguag gcauaaauuu t
21113221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1132aauuuaugcc uacagccucu t
21113321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1133gaggcuguag gcauaaauuu t
21113421DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1134aauuuaugcc uacagccucu t
21113521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1135gaggcuguag gcauaaauuu t
21113621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1136gaggcuguag gcauaaauuu t
21113721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1137gaggcuguag gcauaaauuu t
21113821RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1138ugauaaaacg ccgcagacau u
21113921RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1139ugucugcggc guuuuaucau u
21114021RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1140ugauaaaacg ccgcagacau u
21114121RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1141ugucugcggc guuuuaucau u
21114221RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1142ugauaaaacg ccgcagacau u
21114321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1143ugucugcggc guuuuaucau u
21114421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1144ugucugcggc guuuuaucau u
21114521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1145ccgugugcac uucgcuucau t
21114621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1146ugaagcgaag ugcacacggu t
21114721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1147cgugugcacu ucgcuucacu t
21114821DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1148gugaagcgaa gugcacacgu t
21114921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1149gcacuucgcu ucaccucugu t
21115021DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1150cagaggugaa gcgaagugcu t
21115121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1151ugcacuucgc uucaccucuu t
21115221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1152agaggugaag cgaagugcau t
21115321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1153gaugugucug cggcguuuuu t
21115421DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1154aaaacgccgc agacacaucu t
21115521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1155ugugucugcg gcguuuuauu t
21115621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1156auaaaacgcc gcagacacau t
21115721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1157ugucugcggc guuuuaucau t
21115821DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1158ugauaaaacg ccgcagacau t
21115921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1159cugcugcuau gccucaucuu t
21116021DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1160agaugaggca uagcagcagu t
21116121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1161uccugcugcu augccucauu t
21116221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1162augaggcaua gcagcaggau t
21116321DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1163gaggcuguag gcauaaauuu t
21116421DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1164aauuuaugcc uacagccucu t
21116521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1165gcuguaggca uaaauugguu t
21116621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1166accaauuuau gccuacagcu t
21116721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1167cuguaggcau aaauuggucu t
21116821DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1168gaccaauuua ugccuacagu t
21116921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1169uguaggcaua aauuggucuu t
21117021DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1170agaccaauuu augccuacau t
21117121DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1171ugugcacuuc gcuucaccuu t
21117221DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1172aggugaagcg aagugcacau t
21117321RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1173ugucugcggc guuuuaucau u
21117421RNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1174ugauaaaacg ccgcagacau u
21117521DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1175ugugcacuuc gcuucaccuu t
21117621DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1176aggugaagcg aagugcacau t
21117721DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1177ugucugcggc guuuuaucau t
21117821DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1178ugauaaaacg ccgcagacau t
21117921DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1179gaggcuguag gcauaaauuu t
21118021DNAArtificial SequenceDescription of Artificial Sequence
Synthetic oligonucleotide 1180aauuuaugcc uacagccucu t
2111813221DNAHepatitis B virus 1181ttccactgcc ttccaccaag ctctgcagga
tcccagagtc aggggtctgt attttcctgc 60tggtggctcc agttcaggaa cagtaaaccc
tgctccgaat attgcctctc acatctcgtc 120aatctccgcg aggactgggg
accctgtgac gaacatggag aacatcacat caggattcct 180aggacccctg
ctcgtgttac aggcggggtt tttcttgttg acaagaatcc tcacaatacc
240gcagagtcta gactcgtggt ggacttctct caattttcta gggggatcac
ccgtgtgtct 300tggccaaaat tcgcagtccc caacctccaa tcactcacca
acctcctgtc ctccaatttg 360tcctggttat cgctggatgt gtctgcggcg
ttttatcata ttcctcttca tcctgctgct 420atgcctcatc ttcttattgg
ttcttctgga ttatcaaggt atgttgcccg tttgtcctct 480aattccagga
tcaacaacaa ccagtacggg accatgcaaa acctgcacga ctcctgctca
540aggcaactct atgtttccct catgttgctg tacaaaacct acggatggaa
attgcacctg 600tattcccatc ccatcgtcct gggctttcgc aaaataccta
tgggagtggg cctcagtccg 660tttctcttgg ctcagtttac tagtgccatt
tgttcagtgg ttcgtagggc tttcccccac 720tgtttggctt tcagctatat
ggatgatgtg gtattggggg ccaagtctgt acagcatcgt 780gagtcccttt
ataccgctgt taccaatttt cttttgtctc tgggtataca tttaaaccct
840aacaaaacaa aaagatgggg ttattcccta aacttcatgg gttacataat
tggaagttgg 900ggaactttgc cacaggatca tattgtacaa aagatcaaac
actgttttag aaaacttcct 960gttaacaggc ctattgattg gaaagtatgt
caaagaattg tgggtctttt gggctttgct 1020gctccattta cacaatgtgg
atatcctgcc ttaatgcctt tgtatgcatg tatacaagct 1080aaacaggctt
tcactttctc gccaacttac aaggcctttc taagtaaaca gtacatgaac
1140ctttaccccg ttgctcggca acggcctggt ctgtgccaag tgtttgctga
cgcaaccccc 1200actggctggg gcttggccat aggccatcag cgcatgcgtg
gaacctttgt ggctcctctg 1260ccgatccata ctgcggaact cctagccgct
tgttttgctc gcagccggtc tggagcaaag 1320ctcatcggaa ctgacaattc
tgtcgtcctc tcgcggaaat atacatcgtt tccatggctg 1380ctaggctgta
ctgccaactg gatccttcgc gggacgtcct ttgtttacgt cccgtcggcg
1440ctgaatcccg cggacgaccc ctctcggggc cgcttgggac tctctcgtcc
ccttctccgt 1500ctgccgttcc agccgaccac ggggcgcacc tctctttacg
cggtctcccc gtctgtgcct 1560tctcatctgc cggtccgtgt gcacttcgct
tcacctctgc acgttgcatg gagaccaccg 1620tgaacgccca tcagatcctg
cccaaggtct tacataagag gactcttgga ctcccagcaa 1680tgtcaacgac
cgaccttgag gcctacttca aagactgtgt gtttaaagac tgggaggagc
1740tgggggagga gattaggtta aaggtctttg tattaggagg ctgtaggcat
aaattggtct 1800gcgcaccagc accatgcaac tttttcacct ctgcctaatc
atctcttgta catgtcccac 1860tgttcaagcc tccaagctgt gccttgggtg
gctttggggc atggacattg acccttataa 1920agaatttgga gctactgtgg
agttactctc gtttttgcct tctgacttct ttccttccgt 1980cagagatctc
ctagacaccg cctcagctct gtatcgagaa gccttagaat ctcctgagca
2040ttgctcacct caccatactg cactcaggca agccattctc tgctgggggg
aattgatgac 2100tctagctacc tgggtgggta ataatttgga agatccagca
tccagggatc tagtagtcaa 2160ttatgttaat actaacatgg gtttaaagat
caggcaacta ttgtggtttc atatatcttg 2220ccttactttt ggaagagaga
ctgtacttga atatttggtc tctttcggag tgtggattcg 2280cactcctcca
gcctatagac caccaaatgc ccctatctta tcaacacttc cggaaactac
2340tgttgttaga cgacgggacc gaggcaggtc ccctagaaga agaactccct
cgcctcgcag 2400acgcagatct caatcgccgc gtcgcagaag atctcaatct
cgggaatctc aatgttagta 2460ttccttggac tcataaggtg ggaaacttta
cggggcttta ttcctctaca gtacctatct 2520ttaatcctga atggcaaact
ccttcctttc ctaagattca tttacaagag gacattatta 2580ataggtgtca
acaatttgtg ggccctctca ctgtaaatga aaagagaaga ttgaaattaa
2640ttatgcctgc tagattctat cctactcaca ctaaatattt gcccttagac
aaaggaatta 2700aaccttatta tccagatcag gtagttaatc attacttcca
aaccagacat tatttacata 2760ctctttggaa ggctggtatt ctatataaga
gggaaaccac acgtagcgca tcattttgtg 2820ggtcaccata ttcttgggaa
caagagctac agcatgggag gttggtcatc aaaacctcgc 2880aaaggcatgg
ggacgaatct ttctgttccc aaccctctgg gattctttcc cgatcatcag
2940ttggaccctg cattcggagc caactcaaac aatccagatt gggacttcaa
ccccatcaag 3000gaccactggc cagcagccaa ccaggtagga gcgggagcat
tcgggccagg gctcacccct 3060ccacacggcg gtattctggg gtggagccct
caggctcagg gcatattgac cacagtgtca 3120acaattcctc ctcctgcctc
caccaatcgg cagtcaggaa ggcagcctac tcccatctct 3180ccacctctaa
gagacagtca tcctcaggcc atgcagtgga a 3221
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