U.S. patent application number 17/735010 was filed with the patent office on 2022-09-08 for methods for lowering the infection rate of viruses.
The applicant listed for this patent is Finncure Oy. Invention is credited to Erik Johan Niemela.
Application Number | 20220280439 17/735010 |
Document ID | / |
Family ID | 1000006418750 |
Filed Date | 2022-09-08 |
United States Patent
Application |
20220280439 |
Kind Code |
A1 |
Niemela; Erik Johan |
September 8, 2022 |
METHODS FOR LOWERING THE INFECTION RATE OF VIRUSES
Abstract
According to some embodiments, a method of reducing a likelihood
of a pathogen binding to cell structures of a host comprises at
least partially blocking the pathogen from binding to cell
structures of the host as a result of competitive inhibition by
delivering a carrier to the host, and at least partially reducing
the likelihood of the pathogen binding to target areas of cell
structures of the host.
Inventors: |
Niemela; Erik Johan;
(Helsinki, FI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Finncure Oy |
Helesinki |
|
FI |
|
|
Family ID: |
1000006418750 |
Appl. No.: |
17/735010 |
Filed: |
May 2, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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PCT/FI2021/050259 |
Apr 9, 2021 |
|
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17735010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/711 20130101;
A61K 39/145 20130101; C07K 14/08 20130101; A61K 9/5089 20130101;
C07K 17/14 20130101; A61K 31/7105 20130101; C07K 17/02 20130101;
A61K 9/5078 20130101; A61K 39/215 20130101; A61K 2039/544 20130101;
C07K 17/00 20130101; A61K 9/5192 20130101 |
International
Class: |
A61K 9/51 20060101
A61K009/51; A61K 9/50 20060101 A61K009/50; A61K 31/7105 20060101
A61K031/7105; A61K 31/711 20060101 A61K031/711; C07K 14/08 20060101
C07K014/08 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2020 |
FI |
20205382 |
Feb 19, 2021 |
FI |
20215182 |
Claims
1. A method of reducing a likelihood of a pathogen binding to cell
structures of a host, the method comprising: at least partially
blocking the pathogen from binding to cell structures of the host
as a result of competitive inhibition by delivering a carrier to
the host; wherein the carrier comprises a core having an exterior
surface, a plurality of surface features extending from the
exterior surface of the core, and a plurality of binding sites
along the exterior surface; wherein the surface features are
configured to bind to target areas of cell structures of the host,
wherein binding of the carrier to at least one of the target areas
of cell structures of the host is configured to at least partially
block the pathogen from binding to said target areas; wherein the
surface features at least partially physically mimic
naturally-occurring protrusions of the pathogen; and wherein the
surface features are configured to comprise immune stimulating
properties; and at least partially reducing the likelihood of the
pathogen binding to target areas of cell structures of the host;
wherein a size of the carrier is in the nanometer to micrometer
range.
2. The method of claim 1, wherein the pathogen comprises a
virus.
3. The method of claim 2, wherein the virus is one or more of the
following: a coronavirus, a SARS-CoV-2 virus, an influenza virus, a
rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus.
4. The method of claim 1, wherein the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus or an
allergen.
5. The method of claim 1, wherein the naturally-occurring
protrusions of the pathogen comprise proteins similar to the
protruding proteins at the surface of the viral exterior.
6. The method of claim 1, wherein the carrier is sized, shaped or
otherwise configured to reach targeted portions of the host that
are susceptible to infection by the pathogen.
7. The method of claim 6, wherein the targeted portions of the host
that are susceptible to infection by the pathogen comprise the
lungs or other area of the host's upper or lower respiratory
tract.
8. The method of claim 7, wherein the carrier is configured to be
delivered via the respiratory tract of the host to the targeted
portions of the host that are susceptible to infection by the
pathogen.
9. The method of claim 1, wherein the carrier comprises at least
one coating that improves a binding affinity of the carrier to the
pathogen relative to a binding affinity of the cell structures of
the host to the pathogen.
10. The method of claim 1, further comprising at least one
component positioned at least partially on and/or within
carrier.
11. The method of claim 10, wherein the at least one component
comprises a pharmaceutical agent.
12. The method of claim 11, wherein the pharmaceutical agent
comprises at least one of an anti-viral compound, a nucleic acid
and a RNA or a DNA sequence
13. A method of reducing a likelihood of a pathogen binding to cell
structures of a host, the method comprising: at least partially
blocking the pathogen from binding to cell structures of the host
as a result of competitive inhibition by delivering a carrier to
the host; wherein the carrier comprise a core, surface features
extending from an exterior surface of the core, and a plurality of
binding sites along the exterior surface, wherein the binding sites
are configured to attract at least one portion of the pathogen;
wherein the surface features are configured to bind to target areas
of cell structures of the host to at least partially block the
pathogen from binding to said target areas; wherein the surface
features comprise immune stimulating properties; and wherein the
binding sites are configured to at least partially mimic binding
sites of the host; and at least partially reducing the likelihood
of the pathogen binding to target areas of cell structures of the
host.
14. The method of claim 13, wherein the pathogen comprises a
virus.
15. The method of claim 14, wherein the virus is one or more of the
following: a coronavirus, a SARS-CoV-2 virus, an influenza virus, a
rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus.
16. The method of claim 13, wherein the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus or an
allergen.
17. The method of claim 13, wherein the carrier is sized, shaped
and otherwise configured to reach targeted portions of the host
that are susceptible to infection by the pathogen, the targeted
portions of the host that are susceptible to infection by the
pathogen comprise the lungs or other area of the host's respiratory
tract.
18. The method of claim 17, wherein the carrier is configured to be
delivered via a respiratory tract of the host to the targeted
portions of the host that are susceptible to infection by the
pathogen.
19. The method of claim 13, further comprising at least one
component positioned at least partially on and/or within
carrier.
20. A method of reducing a likelihood of a pathogen binding to cell
structures of a host, the method comprising: at least partially
blocking the pathogen from binding to cell structures of the host
via competitive inhibition by delivering a carrier to the host;
wherein the carrier comprises a core, surface features extending
from an exterior surface of the core, and a plurality of binding
sites along the exterior surface, wherein the binding sites are
configured to attract at least one portion of the pathogen; wherein
the surface features are configured to bind to target areas of cell
structures of the host; and at least partially reducing the
likelihood of the pathogen binding to target areas of cell
structures of the host.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part (CIP) of PCT
Application PCT/FI2021/050259, filed Apr. 9, 2021 and published on
Oct. 14, 2021 as PCT Publ. WO 2021/205077, which claims priority to
Finnish Application Nos. 20205382, filed Apr. 9, 2020 and 20215182,
filed Feb. 19, 2021. The contents of each of the aforementioned
applications are incorporated by reference herein in their
entireties and made part of the present application.
INCORPORATION BY REFERENCE OF MATERIAL IN ASCII TEXT FILE
[0002] This application incorporates by reference the Sequence
Listing contained in the following ASCII text file being submitted
concurrently herewith: File name: FICU002P2_ST25.txt; created on
May 19, 2022 and is 16,687 bytes in size.
BACKGROUND
Field
[0003] The present application pertains to the field of
pharmaceutical products, biologics, medical devices,
over-the-counter drugs and consumer products preventing or reducing
the spread of pathogens, such as, for example, coronaviruses (e.g.,
the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)),
influenzas and viruses causing respiratory infection, diarrhea,
common cold, cytokine storm, general discomfort and/or death,
bacteria, other pathogens and the like. More specifically, the
present application relates to nano- and/or micromaterials-based
carriers, such as mimetic nano- and/or micromaterials-based
carriers, synthesized to minimize the spread of pathogens and
infectious agents (e.g., viruses (e.g., influenzas, rhinoviruses,
noroviruses, respiratory syncytial virus (RSV), SARS-CoV-2, future
strains and/or types of coronaviruses derived thereof, etc.),
bacteria, parasites, antigens, prions, mold, fungi, toxins,
poisons, and allergens.
[0004] The present application also relates to combinatory tailored
treatments of an active pharmaceutical ingredient ("API") loaded
inside a carrier system capable of delivering the drug specifically
to target cells and/or tissues. More specifically this application
pertains to the fabrication and use of man-made materials in the
nano- and/or microscale that would, at least partially, saturate
and bind to receptors, proteins and/or macromolecules at the
cellular level in order to prevent and/or minimize (or reduce the
likelihood of) pathogen binding, in particular, for example, novel
coronaviruses binding and entry to the host target cells and/or
tissues by competitive inhibition.
[0005] The present application further relates to a medical device
or delivery device capable of releasing (e.g., on-demand, specific
amounts of) the synthesized carrier system to targeted tissue or
tissues susceptible to for example coronaviruses. In some
embodiments, for example, such a device includes an inhalation
device, e.g., meter dose, dry inhaler, nebulization,
ultrasonication, nose or mouth drops, or a nasal spray for the
respiratory tract. In some arrangements, the device includes
tailored orally ingestible tablets or solutions for the
gastrointestinal tract, a topically administrable cream or ointment
intended to be applied to a subject's skin and/or an injectable
substance intended to be applied subcutaneously, intravenously,
intraperitoneally or otherwise injected and/or administered using,
at least in part, for example, high pressure or laser.
[0006] Further, the present application relates to synthesized
materials that have the capacity and ability of binding and
encapsulating pathogens or pathogens co-receptors and natural
occurring carriers for, at least partially, immobilizing and
neutralizing the infectious agent for disrupting the infectious
agent. Therefore, according to some embodiments, the carrier system
described herein is configured to reduce the likelihood of
infection of host cells by (1) blocking receptors and/or other
binding sites/features of host cells to which viruses and/or other
pathogens may bind (e.g., for entry into host cells), (2)
delivering immune stimulating properties to target cell
populations, and/or (3) immobilizing viruses and/or other pathogens
by attracting virus and/or other pathogens (e.g., so such viruses
and/or other pathogens are unable to bind to host cells).
Background
[0007] Different pathogens (e.g., viruses, bacterium, parasites,
etc.) prefer environments typical of their specific niche inside
the host tissues. For example, Escherichia. Coli prefers to
colonize the intestine, whereas tuberculosis residues in the lungs
of its host [1]. Malaria-bearing mosquitos may infect their human
host by biting allowing parasites to enter the blood stream and
travel to the liver of the subject for maturation [2]. For the
pathogens to colonize and replicate at their specific environments
and tissues, they need to infect and/or inoculate their host [1-4].
At the cellular level, this mechanism of entry starts by the
pathogen binding or getting in proximity of the host cell where
specific receptors, macromolecules and/or proteins protruding at
the cell membrane facilitates the endocytosis of the infectious
agent. If the specific route of entry is known, such knowledge can
be used for creating a man-made object that can allosterically
hinder the specific pathogens entry by competitive inhibition [5].
For example, by creating a carrier (e.g., nanoparticle), such as a
mimetic nanoparticle, of similar size, surface chemistry and charge
as the pathogen of interest, it is possible to saturate and block
the specific receptors at the host cells hindering the pathogens
entry. Another possibility includes synthetizing man-made materials
(e.g., carriers) that would efficiently bind to the pathogen of
interest encapsulating and immobilizing the infectious agent,
thereby minimizing the possible entry to the host. Another
possibility includes synthetizing man-made materials (e.g.,
carriers) that would efficiently bind to the pathogen, such as the
novel coronavirus and/or co-receptor of interest, thereby
immobilizing the infectious agent and reducing the likelihood (eg.,
minimizing) the possible spread of the disease further inside the
body and/or reducing the likelihood (e.g., preventing) entry to the
host.
[0008] Viruses use components derived from their host for cell
entry. For example, the SARS-CoV-2 virus that causes a respiratory
infection called COVID-19 is decorated by glycoprotein spikes at
the surface of the viral particle. These glycoproteins have high
affinity for the human angiotensin converting enzyme 2 (ACE-2)
allowing for specific internalization of the virus in the
epithelial cells of the respiratory tract, possible intestinal
tract and/or another tract or system of a subject where there is
high expression of its target receptor [3,4]. Thus, potentially
allowing for tailored molecules to be used for intervention of the
SARS-CoV-2 virus enter to its human host. In bacterium it has been
shown that surface topography together with surface charge greatly
influences adhesion that modulates bacterial growth [6]. Using
nanostructured surfaces, it could be possible to control bacterial
adhesion and growth that could be used in medical applications for
preventing infections. Plasmodium falciparum, which is the human
Malaria parasites, uses dynamin like Eps15 homology
domain-containing proteins for hijacking the endocytosis pathways
important for infecting more erythrocytes in its host [2].
[0009] For example, the novel coronavirus SARS-CoV-2, that causes a
respiratory infection called Coronavirus Disease 2019 (COVID-19),
are decorated by glycoprotein spikes at the surface of the viral
particle having high affinity for specific receptor(s). SARS-CoV-2,
SARS-CoV and MERS-CoV belong to the betacoronavirus genus having a
genome size of approximate 30 kilobases encoding both structural
and non-structural proteins. To the structural proteins include the
envelope (E) protein, spike (S) glycoprotein, the nucleocapsid (N)
protein and the membrane (M) protein, whereas to the non-structural
proteins belong, for example, the RNA-dependent RNA polymerase. The
spike (S) glycoproteins decorated on coronaviruses consist of a
homotrimeric transmembrane protein, each 180 kDa monomer comprising
two functional subunits S1 and S2, whereas the S1 unit consists of
two domains: N-terminal domain (NTD) and C-terminal domain (CTD).
Depending on the coronavirus type, either the NTD or CTD of S1 is
used as the receptor binding domain (RBD) capable of binding to
specific receptors at the host cell surface. Each of SARS-CoV-2 and
SARS-CoV utilizes the CTD as its RBD for the human angiotensin
converting enzyme 2 (ACE2) allowing for specific internalization of
the virus in the epithelial cells of the respiratory tract and
possible intestine where there is high expression of its target
receptor [3,4,6]. However, due to the novel amino acid sequence and
structure of SARS-CoV-2. the affinity for the ACE2 receptor is
significantly higher compared to SARS-CoV [6,7]. In both of the
aforementioned coronaviruses, the RBD forms a concave surface that
contains a ridge loop that has the ability to bind to the receptor
binding motif, which is the outer surface of the human ACE2
receptor at its N-terminal helix. In SARS-CoV, this loop contains a
three-residue motif proline-proline-alanine, and these prolines
repeats makes the ridge loop to make a sharp and short turn.
SARS-CoV-2 has a four-residue motif of
glycine-valine/glutamine-glutamate/threonine-glycine that give rise
to two bulkier residues and two flexible glycine residues that
creates a different and compact conformation, allowing the viral
loop to be closer to the ACE2 receptors N-terminal helix forming
additional hydrogen bonds between the loop and the human receptor
resulting in a stronger binding [6]. The S2 subunit from the S
protein is necessary for viral fusion with the host cellular
membrane mediated by proteolytic cleavage by the human
transmembrane serine protease 2 (TMPRSS2), leading to the
internalization of SARS-CoV-2, enabling viral replication inside
its host cell [7]. The inhibitory effect of RBD spike fragment
hexapeptide 438YKYRYL443 (SEQ ID No: 1) of the SARS-CoV-2 has been
estimated to have the highest affinity for ACE2 when compared to
another known coronavirus derived hexapeptides. The specific
hexapeptide YKYRYL (SEQ ID No: 1) carries the dominant binding
amino acid sequence that binds to ACE2 with a high affinity of
KD=46 .mu.M. However, the simulation gives rise to potential
alternative synthetic hexapeptide variants YKYNYI (SEQ ID No: 2)
and YKYNYL (SEQ ID No: 3) with even stronger binding affinity
towards the ACE2 receptor which is highly conserved among different
mammalian organisms allowing transmission from animals to humans
and vice versa [8]. There are variations among human populations
and the animal kingdom regarding the ACE2 receptor in terms of
expression levels and polymorphisms that could influence the
susceptibility of SARS-CoV-2 and outcome of COVID-19 disease
[6-10]. Thus, potentially allowing for tailored molecules to be
used for intervention of the SARS-CoV-2 virus enter to its human
and animal hosts.
[0010] In the context of this specification, both ACE2 and ACE-2
may be understood as referring to human angiotensin converting
enzyme 2.
[0011] Influenza, rhinoviruses, coronaviruses, respiratory
syncytial virus (RSV) and noroviruses are non-limiting examples of
viruses causing respiratory infection, diarrhea, common cold,
cytokine storm, general discomfort, death and/or other symptoms or
ailments. For example, influenza virus is a negative-sense,
single-stranded RNA that causes a respiratory infection commonly
called the "flu" which affects millions of individuals annually and
causes thousands of deaths and millions of hospitalizations. The
flu viral envelope is decorated with the fusion protein
hemagglutinin (HA) that binds to the host sialic acid receptors and
neuraminidase (NA), an enzyme located at the viral surface that
cleaves the glycosidic bonds of the monosaccharide sialic acid,
aiding in penetrating the host mucus and enabling the escape of
newly formed viral particles. The size of influenza virus particles
is around 80-120 nm, which is quite close to the size of
coronaviruses. However, influenzas differ by having two main
proteins on the surface, i.e., HA and NA, whereas coronaviruses
only have the spike proteins protruding on the surface. To further
complicate matters, there are currently 17 different HA proteins
and 10 different NA proteins that have been characterized. It is
these different combinations of proteins that give influenzas their
subtype names. For example, the sequence homology of the HA2
subunit compared to the other HA subtypes is around 51-80%, whereas
the HA1 subunit has an 34% to 59% sequence homology, rendering
different genetic and protein varieties between the influenza
subtypes. Combining the genetic variation with the potential
protein combination of these viruses contributes to the immune
evasive properties of influenzas, rendering efficacious vaccination
development to a difficult task. This limited protection against
influenzas, induced by vaccination, is listed by the Center for
Disease Control (CDC) as follows, "flu vaccination reduces the risk
of flu illness by between 40% and 60% among the overall
population." Therefore, there exists a significant need for
developing anti-viral compounds and broad immune stimulating
influenza vaccines in order to mitigate the spreading of the
flu.
[0012] Rhinoviruses is one category of other major causative agents
for the common cold, and there is currently no efficient
vaccination against these types of viruses. Human Rhinoviruses
(HRV) belong to the picornavirus family and are positive-sense,
single-stranded ribonucleic acid (RNA) viruses that have an
icosahedral symmetry with a particle size of around 30 nm. The
viral capsid is composed of four main proteins: VP1, VP2, VP3, and
VP4, whereas the VP4 protein is located inside of the virus
anchoring the genetic information to the capsid structure. There
are over 150 different serotypes of HRVs with the two most common
types being HRV-A and HRV-B that uses the intercellular adhesion
molecule-1 (ICAM-1) as the cell receptor for entering the host.
However, some of the HRV serotypes use heparin sulfate proteoglycan
as an additional receptor, and there are around 10 serotypes that
use low-density lipoprotein as the cell receptor. Additionally, a
new serotype of HRVs that arose in 2002 was given the name HRV-C,
having a route of cell entry still remains elusive rendering
rhinoviruses to a difficult task to mitigate.
[0013] Respiratory syncytial virus (RSV) belongs to the family of
paramyxoviridae viruses and are negative-sense, single-stranded RNA
viruses that usually cause a mild cold in most healthy humans.
However, for infants, the elderly and/or other humans that are
immunocompromised or otherwise susceptible to disease, the RSV can
cause a more serious disease such as bronchiolitis and pneumonia,
oftentimes leading to hospitalization. The RSVs have an average
size of around 200 nm and contain three membrane proteins: 1) the
host receptor attachment protruding glycoprotein (G), 2) the fusion
protein (F), and 3) a short hydrophobic (SH) protein that forms a
ion channel. RSVs can be further divided into two groups, A and B,
depending on the reaction with monoclonal antibodies directed
against the F and G proteins. The A group is the most prevalent
circulating virus, and the largest genetic divergence is associated
with the gene encoding for the G protein, rendering this protein to
the most variable protein of the virus. This diverse variation of
proteins explains, at least partially, why no effective vaccination
against RSV currently exists on the market. Noroviruses (NoV)
belong to the family Caliciviridae, which are genetically a diverse
group of single-stranded positive-sense RNA that are non-enveloped
viruses that cause an infection commonly called gastroenteritis or
"stomach flu," giving sudden onset of vomiting, diarrhea and other
symptoms, which are often relatively severe. The most common
symptoms for norovirus include nausea, vomiting, stomach pain or
cramps, diarrhea, fever and/or muscle pain, with early symptoms
usually beginning about 12 to 48 hours after exposure to the virus.
Such symptoms can last up to several days. Infected individuals may
continue to shed noroviruses in their feces for several weeks after
recovery, thereby transmitting the disease without knowing to other
individuals. The norovirus consists of an .about.7.7-kb RNA genome
with three open reading frames (ORFs), where ORF1 encodes a
polyprotein precursor which is processed into several nonstructural
proteins, and where the two other ORFs encode the major (VP1) and
minor (VP2) capsid proteins. The viral particles are around 27-30
nm in diameter having an icosahedral symmetry where the viral
capsid is built of 90 dimers consisting of VP1, each protein having
a shell (S) domain and a protruding (P) domain connected by a
flexible linker. The S domain is responsible for the assembly of
the virus capsid shell encapsulating the viral genome and is highly
conserved domain of the VP1 protein. The P domain, on the other
hand, is more variable and includes a P1 and a P2 subdomain. The P1
subdomain binds the S domain with the P2 domain, and the P2
subdomain contains the host receptor binding site which is also a
target for neutralizing antibodies. The norovirus enters its host
by binding to cell-associated glycans located on the cell
membranes, including sialic acid and histo-blood group antigens.
Then soluble cofactors facilitate viral binding to its host
receptor. For murine norovirus (MNoVv), the receptor is a CD3001f
an immunoglobulin (Ig) domain-containing membrane protein, whereas
for the feline calicivirus (FCV), the receptor is a feline
junctional adhesion molecule A (fJAM-A). However, the receptor for
the human norovirus (HNoV) remains elusive. Taking together the
highly variable P2 domain in combination of the VP1 protein's
ability to inhibit cytokine induction and VP2 protein's capability
of regulating antigen presentation and the complex transmission
routes makes noroviruses challenging pathogens to combat.
[0014] Although vaccines can be effective in protecting against
infectious agents, often take significant time and resources to
develop. For example, effective vaccines that can safely be
administered to patients require many clinical tests that need to
be performed before approval. Secondly, vaccinations only work if
the correct antigens for the specific pathogen are being
administered with sufficient immunological reaction, creating an
immunity for the specific disease [11]. For example, seasonal
influenza strains normally vary from one year to the next, and the
vaccines usually contain only a few epitopes of different influenza
strains, thereby rendering the creation of some vaccinations to an
educated guess work.
[0015] Anti-viral medicine can also be effective against viral
infections if treated correctly. However, these medications often
interrupt viral DNA or RNA replication machinery, and thus, it is
not always plausible to use such medicines as a proactive drug.
Unfortunately, these compounds can be harmful for the patient if
used under prolonged periods [12]. Antibiotics are effective
against the spread of bacteria by disrupting their cell division
and/or the synthesis of the proteoglycan-based cell wall [1].
Formulating the most efficient antibiotic depends on if the target
bacterium is gram positive (having a cell wall) or gram negative
(lacking a cell wall). Recently, there have been numerous cases
were multi-resistant bacteria have emerged that are not responding
to traditional antibiotics. In these cases, broad spectrum
antibiotics have been used to combat infection. However, such
strong cocktails of antibiotics can take their toll on the patient
and potentially can give rise to more antibiotic resistance
bacteria [1]. Therefore, there is an unmet need of developing
medications, such as over-the-counter (OTC) drugs and consumer
products, that can be used for preventing or reducing the
likelihood of the spread of pathogens, including mutating novel
coronaviruses, using proactive purposes and having minimal or minor
side effects. Also, the use of tailored medicine using carriers
(e.g., nanomaterials) loaded with an active pharmaceutical
ingredient (API) for both inhibiting the endocytosis of the target
pathogen, in particular viruses, as well as stopping the
replication of already infected cells and/or tissues.
[0016] Protein and proteasome inhibitors show great potential as
these compounds can specificity bind and allosterically hinder the
enzymatic reaction by binding to the active site blocking the
target molecules interaction with the enzyme [13]. However, one of
the major drawbacks of proteasome inhibitors is their instability
and possible low solubility. Further, due to their high
specificity, such molecules often only shows efficacy to only a few
or one specific enzyme per drug molecule.
[0017] Monoclonal antibodies have been used in since 1986. The
first such drug approved by the FDA was Orthoclone OKT3, which is
used for reducing kidney rejection after transplantation.
Monoclonal antibodies that are used in cancer therapeutics include
trastuzumab (Herceptin), which is a drug that binds to the human
epidermal growth factor receptor 2 (HER2) slowing down the growth
of malignant HER2 positive breast cancer cells [14]. The major
limitation of antibody-based therapeutics is that these proteins
are foreign. For example, such therapeutics are produced in mice or
other animals so when they are introduced to patients, they can
invoke an immunologic reaction, potentially giving adverse reaction
of the treatment.
[0018] Nanomedicine shows great potential in the field of targeted
drug delivery, where nanotechnology and medicine are combined for
the development of personalized diagnostics, as well as the
treatment and prevention of different diseases. In some
arrangements, nanomaterials or other carriers include man-made
and/or naturally occurring objects with dimensions between 0.2 nm
to 100 nm. The physical properties of such materials can be
drastically different compared to their bulk counterpart. For
example, nanomaterials can be more reactive on both biological and
chemical substances due to higher surface area to volume ratio.
Functionalized nanoparticles have shown to be able to target
specific cell types opening the possibility of targeted drug
delivery lowering the off-target effects [15]. Combing these
different fields, it would be possible to develop a carrier (e.g.,
a synthetic particle or object) that mimics the pathogen or
pathogens of interest (e.g., viruses, bacteria, other pathogens,
etc.) in order to hinder the spread of the disease by competitive
inhibition. Further, such carriers can be used to advantageously
deliver the appropriate API, drug, molecule and/or other substance
or material to the target tissues with increased efficacy and
minimal or reduced side effects.
SUMMARY
[0019] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host as a result of competitive inhibition
by delivering a carrier to the host, and at least partially
immobilizing the pathogen and reducing the likelihood of the
pathogen binding to target areas of cell structures of the
host.
[0020] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host as a result of competitive inhibition
by delivering a carrier to the host, wherein the carrier comprises
a core having an exterior surface, a plurality of surface features
extending from the exterior surface of the core, and a plurality of
binding sites along the exterior surface, wherein the surface
features are configured to bind to target areas of cell structures
of the host, wherein binding of the carrier to at least one of the
target areas of cell structures of the host is configured to at
least partially block the pathogen from binding to said target
areas, wherein the surface features at least partially physically
mimic naturally-occurring protrusions of the pathogen, wherein the
surface features are configured to comprise immune stimulating
properties, at least partially reducing the likelihood of the
pathogen binding to target areas of cell structures of the host,
and wherein a size of the carrier is in the nanometer to micrometer
range.
[0021] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host as a result of competitive inhibition
by delivering a carrier to the host, wherein the carrier comprise a
core, surface features extending from an exterior surface of the
core, and a plurality of binding sites along the exterior surface,
wherein the binding sites are configured to attract at least one
portion of the pathogen, wherein the surface features are
configured to bind to target areas of cell structures of the host
to at least partially block the pathogen from binding to said
target areas, wherein the surface features comprise immune
stimulating properties, and wherein the binding sites are
configured to at least partially mimic binding sites of the host.
The method further comprises at least partially reducing the
likelihood of the pathogen binding to target areas of cell
structures of the host.
[0022] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host via competitive inhibition by
delivering a carrier to the host, wherein the carrier comprises a
core, surface features extending from an exterior surface of the
core, and a plurality of binding sites along the exterior surface,
wherein the binding sites are configured to attract at least one
portion of the pathogen, and wherein the surface features are
configured to bind to target areas of cell structures of the host,
and at least partially reducing the likelihood of the pathogen
binding to target areas of cell structures of the host.
[0023] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host as a result of competitive inhibition
by delivering a carrier to the host, wherein the carrier comprises
a core having an exterior surface, a plurality of surface features
extending from the exterior surface of the core, and a plurality of
binding sites along the exterior surface, wherein the surface
features are configured to bind to target areas of cell structures
of the host, wherein binding of the carrier to at least one of the
target areas of cell structures of the host is configured to at
least partially block the pathogen from binding to said target
areas, wherein the surface features at least partially physically
mimic naturally-occurring protrusions of the pathogen, wherein the
surface features are configured to comprise immune stimulating
properties, wherein the binding sites are configured to attract at
least one portion of the pathogen, and wherein the binding sites
are configured to at least partially mimic binding sites of the
cell structures of the host. The method further comprising at least
partially immobilizing the pathogen and reducing the likelihood of
the pathogen binding to target areas of cell structures of the
host, wherein the binding sites are recognizable by the pathogen
and are able to be bound by the pathogen, thereby at least
partially immobilizing the pathogen, wherein a size of the carrier
is in the nanometer to micrometer range.
[0024] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host as a result of competitive inhibition
by delivering a carrier to the host, wherein the carrier comprise a
core, surface features extending from an exterior surface of the
core, and a plurality of binding sites along the exterior surface,
wherein the binding sites are configured to attract at least one
portion of the pathogen, wherein the surface features are
configured to bind to target areas of cell structures of the host
to at least partially block the pathogen from binding to said
target areas, wherein the surface features comprise immune
stimulating properties, and wherein the binding sites are
configured to at least partially mimic binding sites of the host.
The method further comprises at least partially immobilizing the
pathogen and reducing the likelihood of the pathogen binding to
target areas of cell structures of the host, wherein the binding
sites are recognizable by the pathogen and are able to be bound by
the pathogen.
[0025] According to some embodiments, a method of reducing a
likelihood of a pathogen binding to cell structures of a host
comprises at least partially blocking the pathogen from binding to
cell structures of the host via competitive inhibition by
delivering a carrier to the host, wherein the carrier comprises a
core, surface features extending from an exterior surface of the
core, and a plurality of binding sites along the exterior surface,
wherein the binding sites are configured to attract at least one
portion of the pathogen, and wherein the surface features are
configured to bind to target areas of cell structures of the host
to, and at least partially immobilizing the pathogen and reducing
the likelihood of the pathogen binding to target areas of cell
structures of the host, wherein the binding sites are recognizable
by the pathogen and are able to be bound by the pathogen.
[0026] According to some embodiments, the pathogen comprises a
virus (e.g., a coronavirus, a SARS-CoV-2 virus, an influenza virus,
a rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus).
[0027] According to some embodiments, the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus, an
allergen or another pathogen.
[0028] According to some embodiments, the naturally-occurring
protrusions of the pathogen comprise proteins similar to the
protruding proteins at the surface of the viral exterior.
[0029] According to some embodiments, the carrier is sized, shaped
or otherwise configured to reach targeted portions of the host that
are susceptible to infection by the pathogen. In some embodiments,
the targeted portions of the host that are susceptible to infection
by the pathogen comprise the lungs or other area of the host's
upper or lower respiratory tract. In some arrangements, the carrier
is configured to be delivered via the respiratory tract of the host
to the targeted portions of the host that are susceptible to
infection by the pathogen.
[0030] According to some embodiments, the carrier comprises at
least one coating that improves a binding affinity of the carrier
to the pathogen relative to a binding affinity of the cell
structures of the host to the pathogen.
[0031] According to some embodiments, the method further comprises
at least one component positioned at least partially on and/or
within carrier. In some embodiments, the at least one component
comprises a pharmaceutical agent (e.g., an anti-viral compound, a
nucleic acid, a RNA or DNA sequence, etc.).
[0032] According to some embodiments, a carrier for reducing a
likelihood of a pathogen binding to cell structures of a host
comprises a core having an exterior surface, a plurality of surface
features extending from the exterior surface of the core, wherein
the surface features are configured to bind to target areas of cell
structures of the host, wherein binding of the carrier to at least
one of the target areas of cell structures of the host is
configured to at least partially block the pathogen from binding to
said target areas as a result of competitive inhibition, and
wherein the surface features at least partially physically mimic
naturally-occurring protrusions of the pathogen, and wherein the
surface features are configured to comprise immune stimulating
properties. The carrier further comprises a plurality of binding
sites along the exterior surface, wherein the binding sites are
configured to attract at least one portion of the pathogen, wherein
the binding sites are configured to at least partially mimic
binding sites of the cell structures of the host, wherein the
binding sites are recognizable by the pathogen and are able to be
bound by the pathogen, thereby at least partially immobilizing the
pathogen and reducing the likelihood of the pathogen binding to
target areas of cell structures of the host, and wherein a size of
the carrier is in the nanometer to micrometer range (e.g., in the
nanometer or micrometer range).
[0033] According to some embodiments, the pathogen comprises a
virus. In some embodiments, the virus includes one or more of the
following: a coronavirus, SARS-CoV-2 virus, an influenza virus, a
rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus.
[0034] According to some embodiments, the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus or an
allergen.
[0035] According to some embodiments, the naturally-occurring
protrusions of the pathogen comprise proteins at the surface of the
viral exterior.
[0036] According to some embodiments, the carrier is sized, shaped
or otherwise configured to reach targeted portions of the host that
are susceptible to infection by the pathogen. In some embodiments,
the targeted portions of the host that are susceptible to infection
by the pathogen comprise the lungs or other area of the host's
upper or lower respiratory tract. In some embodiments, the carrier
is configured to be delivered via the respiratory tract of the host
to the targeted portions of the host that are susceptible to
infection by the pathogen.
[0037] According to some embodiments, the carrier comprises at
least one coating that improves a binding affinity of the carrier
to the pathogen relative to a binding affinity of the cell
structures of the host to the pathogen.
[0038] According to some embodiments, the carrier further comprises
at least one component positioned at least partially on and/or
within carrier. In some embodiments, the at least one component
comprises a pharmaceutical agent (e.g., API). In some embodiments,
the pharmaceutical agent comprises at least one of an anti-viral
compound, a nucleic acid and a RNA or DNA sequence
[0039] According to some embodiments, a carrier for reducing a
likelihood of a pathogen binding to cell structures of a host
comprises a core, surface features extending from an exterior
surface of the core, wherein the surface features are configured to
bind to target areas of cell structures of the host to at least
partially block the pathogen from binding to said target areas as a
result of competitive inhibition, and wherein the surface features
comprise immune stimulating properties. The carrier further
comprises a plurality of binding sites along the exterior surface,
wherein the binding sites are configured to attract at least one
portion of the pathogen, wherein the binding sites are configured
to at least partially mimic binding sites of the host, and wherein
the binding sites are recognizable by the pathogen and are able to
be bound by the pathogen, thereby at least partially immobilizing
the pathogen and reducing the likelihood of the pathogen binding to
target areas of cell structures of the host.
[0040] According to some embodiments, the pathogen comprises a
virus. In some embodiments, the virus includes one or more of the
following: a coronavirus, a SARS-CoV-2 virus, an influenza virus, a
rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus.
[0041] According to some embodiments, the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus or an
allergen.
[0042] According to some embodiments, the carrier is sized, shaped
and otherwise configured to reach targeted portions of the host
that are susceptible to infection by the pathogen, the targeted
portions of the host that are susceptible to infection by the
pathogen comprise the lungs or other area of the host's respiratory
tract.
[0043] According to some embodiments, the carrier is configured to
be delivered via a respiratory tract of the host to the targeted
portions of the host that are susceptible to infection by the
pathogen.
[0044] According to some embodiments, the carrier further comprises
at least one component positioned at least partially on and/or
within carrier (e.g., an anti-viral compound, a nucleic acid, a RNA
or DNA sequence and another pharmaceutical agent, etc.).
[0045] According to some embodiments, a carrier for reducing a
likelihood of a pathogen binding to cell structures of a host
comprises a core, surface features extending from an exterior
surface of the core, wherein the surface features are configured to
bind to target areas of cell structures of the host to at least
partially block the pathogen from binding to said target areas as a
result of competitive inhibition, and a plurality of binding sites
along the exterior surface, wherein the binding sites are
configured to attract at least one portion of the pathogen, wherein
the binding sites are recognizable by the pathogen and are able to
be bound by the pathogen, thereby at least partially immobilizing
the pathogen and reducing the likelihood of the pathogen binding to
target areas of cell structures of the host. According to some
embodiments, the pathogen comprises a virus. In some embodiments,
the virus includes one or more of the following: a coronavirus, a
SARS-CoV-2 virus, an influenza virus, a rhinovirus, a norovirus, a
respiratory syncytial virus (RSV), another virus that impacts the
respiratory system and any other type of virus. According to some
embodiments, the pathogen comprises a bacterium, a parasite, an
antigen, a prion, a mold, a fungus or an allergen. According to
some embodiments, the carrier is sized, shaped and otherwise
configured to reach targeted portions of the host that are
susceptible to infection by the pathogen, the targeted portions of
the host that are susceptible to infection by the pathogen comprise
the lungs or other area of the host's respiratory tract. According
to some embodiments, the carrier is configured to be delivered via
a respiratory tract of the host to the targeted portions of the
host that are susceptible to infection by the pathogen. According
to some embodiments, the carrier further comprises at least one
component positioned at least partially on and/or within carrier
(e.g., an anti-viral compound, a nucleic acid, a RNA or DNA
sequence and another pharmaceutical agent, etc.).
[0046] According to some embodiments, a method of reducing a spread
of pathogens within a host comprises at least partially blocking
pathogens from binding to said target areas as a result of
competitive inhibition by delivering a carrier to the host, wherein
the carrier comprises a core, surface features extending from an
exterior surface of the core, and a plurality of binding sites
along the exterior surface, and at least partially immobilizing
pathogens and reducing the likelihood of pathogens binding to
target areas of cell structures of the host by binding the carrier
to at least one of the pathogens, wherein the surface features are
configured to bind to target areas of cell structures of the host,
wherein the surface features at least partially physically mimic
naturally-occurring protrusions of the pathogen, wherein the
surface features are configured to comprise immune stimulating
properties, wherein the binding sites are configured to attract at
least one portion of the pathogen, wherein the binding sites are
configured to at least partially mimic binding sites of the cell
structures of the host, and wherein, and wherein the binding sites
are recognizable by the pathogen and are able to be bound by the
pathogen.
[0047] According to some embodiments, the pathogen comprises a
virus. In some embodiments, the virus includes one or more of the
following: a coronavirus, a SARS-CoV-2 virus, an influenza virus, a
rhinovirus, a norovirus, a respiratory syncytial virus (RSV),
another virus that impacts the respiratory system and any other
type of virus.
[0048] According to some embodiments, the pathogen comprises a
bacterium, a parasite, an antigen, a prion, a mold, a fungus or an
allergen.
[0049] According to some embodiments, the carrier is sized, shaped
and otherwise configured to reach targeted portions of the host
that are susceptible to infection by the pathogen, the targeted
portions of the host that are susceptible to infection by the
pathogen comprise the lungs or other area of the host's respiratory
tract.
[0050] According to some embodiments, the carrier is configured to
be delivered via a respiratory tract of the host to the targeted
portions of the host that are susceptible to infection by the
pathogen.
[0051] According to some embodiments, the carrier further comprises
at least one component positioned at least partially on and/or
within carrier (e.g., an anti-viral compound, a nucleic acid, a RNA
or DNA sequence and another pharmaceutical agent, etc.).
[0052] According to some embodiments, a carrier for reducing a
likelihood of a pathogen binding to cell structures of a host, the
carrier comprising a core having an exterior surface, a plurality
of surface features extending from the exterior surface of the
core, wherein the surface features are configured to bind to target
areas of cell structures of the host, wherein binding of the
carrier to at least one of the target areas of cell structures of
the host is configured to at least partially block the pathogen
from binding to said target areas as a result of competitive
inhibition, wherein the surface features are configured to at least
partially physically mimic naturally-occurring protrusions of the
pathogen, and wherein the surface features are configured to
comprise immune stimulating properties, and a plurality of binding
sites along the exterior surface, wherein the binding sites are
configured to attract at least one portion of the pathogen, wherein
the binding sites are configured to at least partially mimic
binding sites of the cell structures of the host, wherein the
binding sites are recognizable by the pathogen and are able to be
bound by the pathogen, thereby at least partially immobilizing the
pathogen and reducing the likelihood of the pathogen binding to
target areas of cell structures of the host, and wherein a maximum
cross-sectional dimension of the carrier in at least one dimension
is in the nanometer to micrometer range (e.g., in the nanometer or
micrometer range).
[0053] It is an aim of the present application to control and
hinder (e.g., slow or prevent) the spread of pathogens and other
infectious agents, e.g., viruses, bacteria, parasites, antigens,
proteins, prions, toxins, allergens, other substances that are
foreign and/or potentially harmful and the like. Specifically, the
application provides ways of targeting viruses, such as, for
example, influenzas, rhinoviruses, noroviruses, respiratory
syncytial virus (RSV), coronaviruses (e.g., SARS-CoV-2, future
mutated strains derived from a coronavirus, etc.) and the like,
that could otherwise give rise to disease, infections or allergic
reactions in the host.
[0054] It is an aim of the inventions disclosed herein to decrease
the risk of infection (or at least decrease the spread of infection
if a host has been infected) by a pathogen or pathogens. As such,
various embodiments disclosed herein can be helpful combatting
infection and any resulting symptoms and other consequences (e.g.,
respiratory infection, diarrhea, common cold, cytokine storm, other
inflammatory reactions, general discomfort, intubation, other
symptoms, death, etc.). Accordingly, various embodiments disclosed
herein are configured to, at least partially, resist and otherwise
combat the effects of contracting the COVID-19 disease caused by
SARS-CoV-2 (e.g., via entry of the virus into a host for a
temporary or prolonged duration), to give a targeted treatment for
the specific disease caused by the infectious agent, to provide one
or more additional benefits or advantages, etc.
[0055] Further, it is an aim of the inventions disclosed in the
present application to provide a method for preventing the
spreading and/or for lowering the infection rate of pathogens, such
as SARS-CoV-2, influenzas, rhinoviruses, noroviruses, respiratory
syncytial viruses (RSVs) and/or the like, by, at least in part,
competitive inhibition using synthesized carriers (e.g.,
nanomaterials, particles, objects, etc.).
[0056] Thus, in one aspect, the inventions disclosed herein include
carriers (e.g., synthesized nano- or micro sized materials) that
mimic, at least partially, the pathogen or pathogens of interest,
such as coronaviruses (e.g., SARS-CoV-2), influenzas, rhinoviruses
noroviruses, respiratory syncytial viruses (RSVs) and other viruses
(e.g., viruses capable of causing respiratory infection) using
surface functionalization to hinder or otherwise lower the
likelihood of the infectious agent entering the host. In some
embodiments, carriers can be used to target pathogens other than
viruses, including without limitation, bacteria, parasites,
antigens, prions, mold, fungi, toxins, poisons, and allergens. In
some embodiments, this is accomplished, at least in part, by
competitive inhibition (e.g., at the cellular level).
[0057] It is another aim of the inventions disclosed in the present
application to create a carrier (e.g., man-made particle, object,
material, etc.) that efficiently binds to the pathogen(s) of
interest (e.g., coronavirus) and/or circulating co-receptors (e.g.,
high-density lipoprotein (HDL) receptor in the blood and other
secondary receptors such as the Fc.gamma.R that affects SARS-CoV-2
infection dynamics by antibody-mediated enhancement (ADE)). Thus,
in some embodiments, the carrier at least partially encapsulates
and/or immobilizes the pathogen or other infectious agent and at
least partly hinders the receptor mediated viral entry. In some
embodiments, the carrier is configured to at least partially
inhibit the infectious agent's reproduction capabilities, thereby
reducing the spread of said host organism. In some embodiments, the
carrier makes it easier for the host body to identify, engulf
and/or filter the macromolecule holding the pathogen, resulting in
elimination or neutralization of the infectious agent.
[0058] A synthetic carrier can be used to at least partially
prevent or reduce infection of a host by one or more pathogens,
such as, for example, influenzas, rhinoviruses, noroviruses,
respiratory syncytial viruses (RSVs), corona viruses (e.g.,
SARS-CoV-2), other viruses or pathogens. In some embodiments, the
carrier is configured to bind to target areas of cell surfaces of a
host. For example, the carrier can bind to ACE2 receptors, TMPRSS2
receptors, sialic acid, histo-blood group antigens, ICAM-1, IGF1R
receptors, intracellular or extracellular receptors, other
receptors, or combination of receptors and/or any other portion of
the cell structures of the host that may be susceptible to the
pathogen. According to some embodiments, a carrier is formed by
biocompatible particles having a maximum size in at least one
dimension in the nanometer or micrometer range (e.g., a core of the
carrier includes a maximum size in at least one dimension in the
nanometer or micrometer range). Further, a functionalized surface
can be formed on or along a core of the carrier that is capable of
binding to said target areas of the cell surfaces of the host to at
least temporarily and/or at least partially block the target areas,
thereby, at least partially, preventing or minimizing pathogen
binding and internalization. Accordingly, the risk of the host
being infected or contracting a disease caused by said pathogen,
such as a virus, can be beneficially reduced.
[0059] In an aspect, the present application provides for loading
of synthetic particles (e.g., carriers) with API or molecules, such
as for example and without limitation, Celastrol, anti-viral drugs,
Zinc and/or immune stimulating molecules such as, for example,
Interferon-Gamma modulators alternatively administering RNA vectors
encoding Interferon-Gamma producing said protein in the host,
anti-viral compounds that prevent the spread of (and/or hinder the
replication of) the targeted pathogen or pathogens (e.g.,
coronavirus, influenzas, rhinovirus, noroviruses, respiratory
syncytial virus, etc.) inside the host body and/or the like.
[0060] It is another aim of the inventions disclosed in the present
application to provide a medical device capable of delivering the
synthetized carrier, particle, object or other material (e.g.,
on-demand by the patient or other user). For example, in some
embodiments, such a medical device comprises an inhalation device,
an aerosol, a spray, eye or oral drops, an intravenous injection, a
tablet, a topically applicable cream, an ointment or other
material.
[0061] It is another aim of the inventions disclosed in the present
application to provide a medical countermeasure similar to that of
chelating agents used in toxifications of metal complexes (e.g.,
arsenic poisoning, snake venoms, mold toxins, etc.) [16]. In some
embodiments, the present inventions provide a functionalized
nanomaterial or carrier, which, in some configurations, is
effectively an antidote capable of binding toxic components of a
specific virus to larger entities that can be metabolized, degraded
or secreted from the body and/or capable of binding to viral
co-receptors inside the host to minimize or otherwise reduce
potential spreading inside the organism [15]. The antidote (e.g.,
nanomaterial or other carrier) can be inhaled, orally ingested or
administered through intravenous injection and/or any other
delivery method or technology (e.g., inhalation, ingestion, topical
application, etc.), as desired or required.
[0062] It is another aim of the inventions in the present
application to provide a medical countermeasure similar to that of
chelating agents used in toxifications of metal complexes (e.g.,
arsenic poisoning, snake venoms, mold toxins and the like). In some
embodiments, the present inventions provide a carrier (e.g., a
functionalized nanomaterial) that acts as an antidote, and is
advantageously capable of binding toxic metal complexes, toxins,
poisons and/or the like to larger entities that can be metabolized,
degraded and/or secreted/otherwise removed from the body [15]. The
antidote (e.g., carrier or nanomaterial) could be inhaled, orally
ingested, administered to the host using intravenous injection
and/or any other delivery method or technology.
[0063] In some embodiments, a carrier (e.g., a functionalized
nanoparticle) is loaded, coated and/or decorated with an API and/or
RNA/DNA and/or other molecules or materials capable of binding to
cell structures of the host (e.g., receptors of the host's cell
structures) and delivering its cargo or contents to targeted cell
population. Beneficially, this can at least partially block or
otherwise limit entry of a specific pathogen, such as, for example,
influenzas, rhinoviruses, noroviruses, respiratory syncytial
viruses, coronaviruses and other viruses causing infection (e.g.,
in the respiratory tract or other anatomical location). Further the
use of such carriers can advantageously provide the capability of
releasing certain materials (e.g., APIs, therapeutics, other
molecules, etc.) to the host thereby minimizing or at least
reducing the spread of the infectious agent.
[0064] According to some embodiments, the present application
discloses a carrier (e.g., a polymeric or protein/peptide
functionalized nano and/or micro particle) that is loaded with one
or more anti-viral molecules capable of binding to one or more
receptors and/or other portions of a host cell structure (e.g.,
ACE2 and/or TMPRSS2 receptors, sialic acid, histo-blood group
antigens, ICAM-1, IGF1R receptors, other receptors in humans that
at least partially hinder (e.g., allosterically hinder) the
targeted virus or other pathogen (e.g., influenza, rhinovirus,
norovirus, respiratory syncytial virus, SARS-CoV-2 or another
corona virus) from binding to its target receptor). As a result,
the risk of infecting the host can be reduced, e.g., for a limited
or prolonged duration.
[0065] Certain advantages are obtainable as a result of the present
inventions, as carriers (e.g., nanoparticles, other particles or
objects, etc.) can be synthetized using different materials and/or
functionalized (or otherwise configured) with virtually endless
combinations of features and/or functionality. In some embodiments,
the carriers include mesoporous silica nanoparticles (MSNs) or
other inorganic silica-based materials which have shown great
potential for targeted drug delivery. For example, MSNs can have
tunable ordered repetitive mesostructures of pores that can be
loaded with different drugs and/or other components or materials.
In some arrangements, such carriers or particles can be synthesized
in various sizes, shapes and/or other configurations, as desired or
required for its particular purpose or application. Furthermore,
inorganic silica materials, such as MSNs, are safe, biocompatible,
stable, customizable and versatile. For instance, inorganic silica
materials have been given a Generally Recognized As Safe (GRAS)
designation by the FDA as silica degrades in aqueous solution to
silicic acid and gets excreted or otherwise removed (e.g., via the
urine), and is, therefore, considered biocompatible [15]. In some
embodiments, since MSNs and other inorganic silica-based materials
have been proved to be a versatile delivery vehicle with beneficial
features and properties (e.g., improved stability, large surface
area, tunable pore sizes and volumes, capable easy encapsulation of
drugs, proteins, biogenic molecules, etc.), they are well suited to
be used in carriers.
[0066] In some embodiments, the carriers comprise lipid-based
micelles (e.g., forming the cores of the carriers). Such carriers
can be provided by synthetizing, for example, cholesterol based
lipid particles decorated with SARS-CoV-2 spike protein fragments
that bind both to ACE2 and TMPRSS2 as well as to cholesterol and
its high-density lipoprotein (HDL) scavenger receptor B type 1
(SR-B1) and/or Fc.gamma.R receptor. These co-receptors can
facilitate ACE2-dependent entry of the carrier (e.g., the
envisioned nanoparticle) loaded with one or more selected APIs for
combating a targeted disease (e.g., COVID-19 disease). In some
embodiments, advantageously, by creating a carrier (e.g., a
nanoparticle and/or microparticle) that competes with the spike
protein-HDL interaction, the ability of SARS-CoV-2 for
ACE2-mediated internalization is lowered and viral entry to host
cells is blocked and replication hindered.
[0067] In some embodiments, the carriers comprise solid lipid
particles synthetized by microfluidics and/or protein-based
particles such as ferritin-based particles that self-assembly
decorated or conjugated with viral mimicking protrusion capable of
both binding to the target receptor and stimulating the host immune
system against the said virus.
[0068] In some embodiments, carriers comprise quantum nanoparticles
(e.g., as a core). Such quantum particles or carriers once
decorated or otherwise provided with the desired surface features
(e.g., SARS-CoV-2 or other viral spike protein receptor binding
domain (RBD)) can be capable of binding to ACE2 receptors, other
receptors and/or other binding sites of the host cell structure.
Accordingly, such carriers can be internalized (e.g., by ACE2-GFP
HEK293T cells after a certain time period, for example,
approximately 3 hours), thereby validating that it is possible to
produce man-made virus-like particles that efficiently bind and are
internalized by target cells. Furthermore, protein-lipid entities,
such as Dalbavancin, an antibiotic, can bind to the ACE2 receptor
(or another receptor or binding site) to prevent or reduce the
likelihood that the targeted pathogen (e.g., SARS-CoV-2) is able to
enter its host via intervening viral-receptor interactions.
[0069] In some arrangements, carriers (e.g., nano-sized and/or
micro-sized materials) are synthesized that mimic (e.g.,
accurately, approximately) the targeted pathogen by using, for
example, the known size, morphology, surface properties and/or
other properties of the infectious agent. Thus, a man-made carrier
(e.g., particle, object) can be produced that at least partially
hinders or otherwise mitigates the spread of the disease caused by
the target infectious agent (e.g., virus, bacterium, other
pathogen) by competitive inhibition. In some embodiments, such
man-made carriers (e.g., particles, materials, etc.) are configured
to (i) bind to receptors or other binding sites of host cell
structures, thereby blocking the attachment of pathogens to such
receptors or binding sites and preventing (or lowering the
likelihood of) the infectious agent from entry into the cell
structure and/or (ii) bind to the infectious agent itself thus
immobilizing the threat caused by the infection agent. Accordingly,
the carrier embodiments disclosed herein and equivalents thereof
provide two possible approaches to reducing infection of a host's
cells, and as such, have immense potential in different
applications in medicine, drug development, medical devices,
consumer, sanitation products and/or the like.
[0070] According to some embodiments, it is possible to synthetize
nano-sized and/or micro-sized materials (e.g., carriers, particles,
objects) that mimic, at least partially, targeted viruses or other
pathogens (e.g., SARS-CoV-2 virus, the spread of which resulted in
a global epidemic starting in 2020, pandemic strain/type of the
influenzas, rhinoviruses, noroviruses, respiratory syncytial
viruses, coronaviruses (including mutated forms thereof) derived
from SARS-CoV-2, other viruses, other pathogens, etc.) by using the
known size, morphology, surface properties and/or other
characteristics or properties of the targeted virus or other
pathogen. Thus, carriers (e.g., man-made particles or objects) can
beneficially hinder or at least slow the spread of the disease by
competitive inhibition.
[0071] In some embodiments, such carriers (e.g., man-made
materials) are designed and otherwise configured to bind to surface
receptors, co-receptors and/or other binding sites of a host cell
structure, and thereby blocking, at least partially, the entry of
the virus or other pathogen. In some arrangements, in addition to
binding to host cell structures (and thus at least partially
blocking or preventing the attachment of a pathogen to said host
cell structures) and/or immobilizing the pathogen by binding to the
pathogen itself, carriers are configured to simultaneously
administer or otherwise deliver APIs and/or other materials. Such
APIs and/or other materials delivered to target cells and tissues
can be configured to create an environment that is hostile to viral
replication and that provides a synergistic approach to the host.
Such carriers and the associated methods of treatment can have
immense potential in different applications in medicine, drug
development, medical devices, consumer products and the like. In
some embodiments, for instance, adding Zinc ions, Celastrol
Cannabinols, anti-viral molecules, other APIs and/or other
substances or materials to the nanoparticle or other carrier, it
would be possible to create an environment for at least partially
arresting the viral replication cycle inside host cells (e.g.,
cells that are expressing ACE2 receptors or other targeted
receptors on their cell surface).
[0072] In some embodiments, a carrier (e.g., a synthetic
nanoparticle and/or microparticle) can be used to reduce the spread
of influenzas, rhinoviruses, noroviruses, respiratory syncytial
viruses (RSVs), coronaviruses (e.g., SARS-CoV-2, other derived
coronaviruses), other viruses that cause symptoms such as
respiratory infection, diarrhea, common cold, cytokine storm,
general discomfort, serious illness, death and/or any other viruses
or other pathogens. To that end, in some embodiments, the synthetic
particles or other carriers can be manufactured to match, imitate,
emulate or substantially match, imitate or emulate one or more
characteristics or other properties of one or more targeted
pathogens (such as, for example, influenzas, rhinoviruses,
noroviruses, respiratory syncytial viruses (RSVs), coronaviruses
(e.g., SARS-CoV-2 virus) and/or any other viruses or other
pathogens). More specifically, according to some arrangements, the
particle or carrier is preferably fabricated to a size of around 10
to 200 nm, for example 50 to 150 nm (such as around 100 to 120 nm),
10 to 200 nm, 10 to 100 nm, 100 to 200 nm, 50 to 200 nm, 10 to 150
nm, values between the foregoing values and ranges).
[0073] Further, in some embodiments, the carriers can be coated
with similar amino acids and peptides as the targeted virus and/or
other pathogen. For example, in some embodiments, the carrier can
contain glycoprotein spike proteins, other protrusions, similar
molecules and/or other surface features. In some embodiments, such
features of the carrier can be configured to mimic or substantially
mimic certain surface features of the viral envelope. More
specifically, in some embodiments, the particle is preferably
fabricated to a size of around 100-120 nm and coated with similar
amino acids and peptides as the virus contains, for example,
glycoprotein spikes, protrusions and/or other features at the viral
surface or similar molecules that mimic the surface of the viral
envelope. In some embodiments, the carrier (e.g., particle or
object) is fabricated to a size of around 100 nm (e.g., 80 to 120
nm, 90 to 110 nm, 100 nm, values between the foregoing, etc.) and
is coated with similar amino acids and peptides as the targeted
virus or other pathogen (e.g., glycoprotein spikes and/or
protrusions at the viral surface or similar molecules that mimic
the surface of the viral envelope). In more specific embodiments,
the carrier (e.g., object or particle) is fabricated to a size of
around 0.2 to 100 nm and coated with similar amino acids and
peptides as the virus contains e.g. protrusions at the viral
surface.
[0074] Next, certain embodiments will be described in more
detail.
BRIEF DESCRIPTION OF THE DRAWINGS
[0075] These and other features, aspects and advantages of the
present application are described with reference to drawings of
certain embodiments, which are intended to illustrate, but not to
limit, the present inventions. It is to be understood that these
drawings are for the purpose of illustrating the various concepts
disclosed herein and may not be to scale.
[0076] FIG. 1 is a schematic depiction of different applications of
synthetized nanomaterials according to some embodiments of the
present technology;
[0077] FIG. 2 is a schematic depiction of infection prevention and
control by competitive inhibition using synthetic nanoparticles
according to some embodiments of the present technology;
[0078] FIG. 3 is a schematic depiction of immobilization of an
infectious agent by functionalized nanomaterials according to some
embodiments of the present technology;
[0079] FIG. 4 is a schematic depiction of dual targeting strategy
compromising both immobilization of an infectious agent and by
infection prevention and control by competitive inhibition
functionalized nanomaterials according to some embodiments of the
present technology;
[0080] FIG. 5 schematic depiction of utilization of nanoparticles
coated with peptides resembling the binding motif of the spike
protein from the SARS-CoV-2 virus for encapsulating and
immobilization of the co-receptor and as a consequence decrease the
virus mobility, thus minimizing the risk of the virus's infecting
the host cells or infecting the host to other organs;
[0081] FIG. 6 is a schematic depiction of functionalized
nanoparticles mimicking SARS-CoV-2 to be used as targeted
intervention and therapy against COVID-19 and other respiratory
diseases according to some embodiments of the present technology;
and
[0082] FIG. 7 shows an example of a SARS-CoV-2 spike RBD expression
construct. Different expression cassettes (shown as the XXX region)
can be used for expressing the desired construct e.g. influenza H7
haemagglutinin (indicated as "Signal sequence"), Tag, spacer, and
SARS-CoV-2 RBD.
DETAILED DESCRIPTION
[0083] In the present context, the term "around" means, when used
in connection with numerical values, that a variation of .+-.25%,
in particular .+-.20%, for example .+-.10%, or .+-.5%, of the exact
value is included by a literal reading of that value.
[0084] In the present context, the term "about" means, when used in
connection with numerical values, that a variation of .+-.25%, in
particular .+-.20%, for example .+-.10%, or .+-.5%, of the exact
value is included by a literal reading of that value.
[0085] The term "polymer" is used herein in a broad sense and
refers to materials, compounds, amino acids and proteins
characterized by repeating moieties or units.
[0086] The term "functionalization" is used herein in a broad sense
and refers to conjugating, coating, covalently and/or otherwise
adding (e.g., allosterically adding) materials, compounds, drugs,
amino acids and/or proteins to the synthetized particle or
object.
[0087] The term "biocompatible" refers herein to "the ability of a
material to perform with an appropriate host response in a specific
application" (e.g., William's definition) [19].
[0088] Nanomaterials and nanomedicine can be classified according
to the targeting strategies used, which can include, for instance,
active or passive targeting. In some embodiments, passive targeting
utilizes non-functionalized particles for accumulation in organs
and tissues that are responsible for clearance of foreign objects
such as macrophages, e.g., in the liver, spleen, etc. In some
arrangements, tumor microenvironments typically show an enhanced
permeability and retention effect (EPR), which can be a consequence
of leaky and fenestrated blood vessels around tumors. Active
targeting, on the other hand, uses a targeting ligand or
functionalization that enhances the accumulation of the carrier at
target site [15].
[0089] There are virtually endless functionalization possibilities
by covalently attaching, adhering, saturating or binding (e.g.,
allosterically binding) molecules, polymers, proteins, amino acids,
compounds and/or drugs onto the nanomaterial for achieving active
targeting. One of the major advantages of functionalizing a smaller
molecule to a larger entity, e.g., antibody or hydrophobic
molecules to a nanomaterial, is to increase the combined objects
stability and/or solubility and/or possible minimize the unwanted
immunologic reaction [15].
[0090] Described herein are carriers (e.g., fabricated
nanomaterials or other carriers) used for inhibiting or improving
the ability to inhibit, at least partially, pathogen entry of
certain pathogens or other unwanted organisms, in particular
coronaviruses (e.g., SARS-CoV-2), influenzas, rhinoviruses,
noroviruses, respiratory syncytial viruses and other viruses
causing respiratory infection to the host organism. Accordingly,
such nanomaterials or other carriers can be advantageously used to
limit or reduce the replication and spread of a disease or
virus.
[0091] Embodiments disclosed herein have capabilities of carrying
or otherwise delivering or providing anti-pathogenic
pharmaceuticals or other materials, such as anti-viral drugs, in
the carrier (e.g., nanomaterial) to reduce the replication and
growth of the infectious agent.
[0092] Embodiments disclosed herein pertain to the fabrication of
man-made (e.g., fabricated) carriers or materials (e.g., in the
nano- and/or microscale) that are configured to at least partially
saturate and bind to receptors, proteins and/or macromolecules at
the cellular level in order to reduce the likelihood (e.g.,
prevent) and reduce (e.g., minimize) pathogens (e.g., coronavirus)
binding to and/or entering into receptors and/or target tissues of
the host. In some embodiments, the synthesized carrier (e.g.,
nanomaterial) can be stored and loaded onto a medical device
capable of releasing (e.g., on-demand, specific amounts) the
synthesized carrier system to specific tissue. Such medical devices
or other devices or systems include, without limitation, inhalation
devices, oral tablets, injectable substances, lotions or creams
and/or any other device, system or component, as desired or
required.
[0093] In one aspect or embodiment, a synthetic carrier, particle
or object is configured to at least partially hinder or impede the
spread of the COVID-19 disease by competitive inhibition and to
deliver an API, drug or molecule to targeted cells and/or tissues
with increased or improved efficacy. In some embodiments, the use
of such carriers, particles or objects is configured to have few or
minimal side effects for creating a hostile environment for the
virus or other targeted pathogen. According to some arrangements,
the carrier or particle (e.g., the mimetic nanoparticle) is
functionalized with, in one non-limiting example, hexapeptide
resembling that of the RBD from SARS-CoV-2. This can, according to
some embodiments, allow high binding affinity to the ACE2 receptor
at the lining of the respiratory system, thus blocking, at least
partially, a route (e.g., a primary route) of infection. In some
embodiments, this approach virtually eliminates the problem
associated with mutations of the viral strain, because the specific
target is the human receptor and not the constantly evolving
coronavirus. This may be especially significant, for instance, in
light of the impactful SARS-CoV-2 mutations that have appeared
starting in 2021 and beyond, which have and will have a significant
impact on the state of world health. Alternatively or
simultaneously, ACE2 receptor binding moieties or antibodies
designed to bind and immobilize the virus at specific sites can be
used.
[0094] Therefore, in some embodiments, as noted above and discussed
in greater detail herein, carriers (e.g., particles, obstacles,
etc.) are configured to prevent or reduce the likelihood of
infection by pathogens using one or more principles or mechanisms.
For example, in some arrangements, the carriers are sized, shaped
and otherwise configured to prevent or reduce the likelihood of
pathogen infection by competitive inhibition (e.g., blocking
receptors).
[0095] In another aspect or embodiment, a carrier (e.g., a
synthetic particle or object) is configured to deliver its "cargo"
or content to targeted cell population. For example, in some
arrangements, the carrier comprises a core material that can be
"loaded" or otherwise provided with (e.g., into or onto) drugs, API
and/or other molecules or materials. Such substances provided in
and/or on the carrier can be targeted with higher efficacy to
specific cells and tissues using, for example, functionalization
(e.g., protrusions that are capable of binding to host cell
structures such as receptors that facilitates carrier uptake at
said cells enabling targeted therapeutics). Thus, potentially, the
therapeutic effect of the drug can be improved, increased or
otherwise enhanced, e.g., by accumulating the local dosage in
specific cells, reducing at least some side-effects of the drug
(e.g., by reducing off-target effect in unwanted cells and/or the
like).
[0096] In another aspect or embodiment, a carrier (e.g., a
synthetic particle or object) is configured to hinder, at least
partially, the spread of influenza or the "flu" by competitive
inhibition and/or immobilizing the virus. As noted above, in some
arrangements, the size of the carrier (e.g., the particle or
object) is similar or substantially similar to the size of the
virus or other pathogen being targeted. For example, a diameter or
other cross-sectional dimension of the carrier can be 50% to 200%
(e.g., 50-200, 50-100, 50-150, 50-200, 100-150, 150-200%, values
and ranges between the foregoing, etc.) of the diameter or other
cross-sectional dimension of influenza or other targeted virus or
pathogen.
[0097] In some embodiments, the carrier is loaded with or otherwise
comprises an API, drug, molecule and/or other materials to be
delivered to target cells and tissues with increased efficacy and
with minimal or reduced side effects, while creating a hostile
environment for the virus. However, in other arrangements, the
carrier (e.g., particle or object) does not contain any API, drug
or other molecule that is intended to be delivered to targeted
cells and tissues. Even in such embodiments, the carriers or
particles can be configured to reduce the likelihood of infection
(e.g., by preventing the actual virus from binding to and infecting
targeted cells of the host). This can be accomplished by
immobilizing the targeted virus (e.g., using a carrier that is
configured to bind to the targeted pathogen) and/or by blocking
receptor (or other binding sites or portions) of host cells. The
mimetic carrier or particle can be functionalized with, for example
and without limitation, protein fragments resembling HA and NA
binding moiety. In such embodiments, high binding affinity to the
host sialic acid receptors at the lining of the respiratory system
if facilitated, thereby at least partially blocking a route (e.g.,
the primary route) of infection. Alternatively or simultaneously,
sialic acid receptor binding moieties or antibodies designed to, at
least partially, bind and immobilize the virus at one or more host
receptor binding moieties, receptor binding domains and/or other
sites can be used.
[0098] In another aspect, a carrier (e.g., a synthetic particle or
object) mimics (or is configured or adapted to mimic), for example,
Rhinoviruses in order to hinder, at least partially, the spread of
the major causative agent of the common cold by competitive
inhibition. In some embodiments, the appropriate API, drug or
molecule is delivered to target cells and tissues with increased
efficacy and with minimal or reduced side effects while creating a
hostile environment for the virus. The mimetic particle (e.g.,
carrier) can be functionalized with, for example, but not limited
to, VP1 and VP2 capsid protein allowing high binding affinity to
the ICAM-1 and other related receptor at the lining of the
respiratory system. Thus, the primary route of infection can be, at
least partially, blocked. Alternatively or simultaneously, ICAM-1
receptor binding moieties or antibodies designed to bind and
immobilize the virus at host receptor binding moiety, receptor
binding domain or other sites can be used.
[0099] In another aspect, a carrier (e.g., a synthetic particle or
object) mimics (or is configured to mimic), at least approximately
or substantially, respiratory syncytial virus (RSV) in order to
hinder, at least partially, the spread of influenza or the "flu," a
respiratory disease, by competitive inhibition. In some
embodiments, with the use of such carriers, the appropriate (e.g.,
desired, required, etc.) API, drug or molecule is delivered to
target cells and tissues with increased efficacy and with minimal
or reduced side effects while creating a hostile environment for
the virus. The envisioned carrier (e.g., mimetic particle or
object) functionalized with, for example and without limitation,
receptor attachment protruding glycoprotein (G) allowing high
binding affinity to the IGF1R receptor at the lining of the
respiratory system. Accordingly, such a carrier can be configured
to block, at least partially, the primary route of infection.
Alternatively or simultaneously, IGF1R receptor binding moieties or
antibodies designed to bind and immobilize the virus at other sites
than the host receptor binding moiety can be used.
[0100] In another aspect, a carrier (e.g., a synthetic particle or
object) mimics or is configured or adapted to mimic) Noroviruses.
In such embodiments, the carrier can hinder, at least partially,
the spread of "stomach flu" a gastroenteritis disease by
competitive inhibition. In some embodiments, with the use of such
carriers, the appropriate (e.g., desired, required, etc.) API, drug
or molecule is delivered to the target cells and tissues with
increased efficacy and with minimal or reduced side effects while
creating a hostile environment for the virus. The carrier (e.g.,
the envisioned mimetic particle) functionalized with, for example
and without limitation, VP1 containing the P2 subdomain allowing
high binding affinity to the including sialic acid and histo-blood
group antigens at the lining of the respiratory system. Thus, the
carriers can block, at least partially, the primary route of
infection. Alternatively or simultaneously, sialic acid receptor
binding moieties or antibodies designed to bind and immobilize the
virus at host receptor binding moiety, receptor binding domain or
other sites can be used.
[0101] FIG. 1 schematically shows some non-limiting applications of
synthetized carriers (e.g., nanomaterials, objects, particles,
etc.) according to some embodiments of the present technology.
Thus, by way of an example, the carrier (e.g., nanomaterial) can be
loaded with one or more active pharmaceutical ingredients (API),
such as, e.g., Celastrol, Zinc, anti-viral compounds,
Interferon-Gamma modulators, etc., and then used in inhalation
devices, oral tablets or injectables, or other devices or tools of
administering the carriers, to name just a few. Such nanomaterials
and/or micromaterials can be used to hinder, at least partially,
the entry of novel coronaviruses within host cells, thereby
reducing or minimizing the spreading of the disease.
[0102] Embodiments disclosed herein allow for decreasing the risk
of a pathogen or pathogens, such as coronaviruses, influenzas,
rhinoviruses, other viruses causing respiratory infection (e.g.,
SARS-CoV-2), entering its host for a temporary or prolonged
duration. Accordingly, such embodiments can advantageously give a
targeted treatment for the specific disease caused by the
infectious agent.
[0103] In a first embodiment, a synthetic carrier is provided,
which comprises biocompatible particles having a maximum size in at
least one dimension in the nanometer or micrometer range. In some
embodiments, said maximum size in at least one dimension is 10 to
500 nanometers (e.g., 10 to 500, 10 to 50, 10 to 100, 50 to 100, 1
to 100, 100 to 200, 200 to 300, 300 to 400, 400 to 500, 200 to 400
nanometers, values and ranges between the foregoing, etc.). In some
embodiments, such carriers form or include a core and include a
functionalized surface capable of binding to target areas of cell
surfaces of a host. Advantageously, such binding can at least
temporarily block the target areas to prevent or minimize pathogens
(e.g., influenzas, rhinoviruses, coronaviruses including but not
limited to SARS-CoV-2, other viruses causing respiratory infection,
thereby reducing the risk of the host contracting the disease
caused by the pathogen (e.g., the COVID-19 disease, diarrhea,
respiratory infections, common cold, etc.).
[0104] As used herein, the term "host" means, but is not
necessarily limited to, an individual mammal, in particular a human
or an animal.
[0105] As schematically illustrated in FIG. 2, in some embodiments,
the carrier 10 comprises a core 20 and a plurality of surface
features 30 related to the core. As disclosed herein, the surface
features can include protrusions that resemble or mimic, at least
partially, spike proteins or other protrusions or features of a
target virus or other pathogen. With continued reference to FIG. 2,
the carrier 10 can be "loaded" or otherwise provided with one or
more materials or other substances (e.g., APIs, other
pharmaceuticals or agents, etc.) 40. As disclosed herein, such
materials 40 can be delivered by the carrier to or near the site of
a targeted virus or other pathogen for improved treatment (e.g.,
therapeutic treatment, infection prevention or mitigation,
etc.).
[0106] In some embodiments, the synthetic carrier comprises a
"nano" material which can be of nano- or micrometer or larger size.
In some arrangements, the synthetic carrier has a size in at least
one dimension which is in the nanometer scale. In some
arrangements, the synthetic carrier has a size in at least one
dimension which is in the micrometer scale. For example, such a
size in at least one dimension is schematically depicted in FIG. 2
as dimension D. In other embodiments, the carrier has a size in at
least one dimension that is outside the nanometer or micrometer
range, as desired or required. For instance, the carrier can have a
size in at least one dimension which is smaller than one nanometer
(e.g., in the picometer range or smaller) or greater than one
millimeter, depending on the targeted pathogen or other factors.
The nanomaterial or other synthetic carrier can be formed as a
particle, spheroid, cubical, cigar-shaped, elongated, triangle,
sharp and pointy, a sheet and film and/or any configuration or
shape.
[0107] According to some embodiments, a maximum cross-sectional
dimension of the core 20 of the carrier 10 is 10% to 1000% (e.g.,
10 to 1000, 500 to 1000, 10 to 500, 50 to 150, 10 to 300, 100 to
500, 10 to 100, 75 to 125%, values between the foregoing, etc.) of
a maximum cross-sectional dimension of the pathogen (e.g., virus,
bacterium, other pathogen, etc.).
[0108] In some embodiments, the synthetic carrier has a maximum
size in at least one dimension which is smaller than 2500 .mu.m
(e.g., less than 2500 .mu.m, less than 2000 .mu.m, less than 1500
.mu.m, less than 1000 .mu.m, less than 500 .mu.m, less than 100
.mu.m, less than 50 .mu.m, less than values between the foregoing,
etc.). In one embodiment, the material has a maximum size in at
least one dimension which is smaller than 10 .mu.m (e.g., less than
10 .mu.m, less than 5 .mu.m, less than 1 .mu.m, less than values
between the foregoing, etc.). In one embodiment, the material in
particular nanomaterial has a maximum size in at least one
dimension which is smaller than 1000 nm, in particular smaller than
around 500 nm or around 100 nm or smaller than around 10 nm or
smaller than around 0.2 nm.
[0109] In one embodiment, the synthetic carrier is biocompatible.
For example, according to some arrangements, such a material is
configured to cause no reaction or only a minor unwanted reaction
in the end-user (e.g. toxicity, off-target effects, etc.).
[0110] Generally, in some embodiments, the carriers disclosed
herein are synthetic, which is used interchangeably with
"synthesized" to denote that they are man-made or non-natural.
[0111] Embodiments of the carriers comprise organic or inorganic
materials, protein based, ferritin protein particles, lipid
droplets, micelles, solid lipids, or any combination of these.
[0112] The synthetic material can be selected from inorganic and
organic, monomeric and polymeric materials capable of forming
biocompatible nano- or micro-sized particles as explained
herein.
[0113] Examples of materials for the carriers comprise one or more
of the following: synthetic polymers (e.g., thermoplastic or
thermosetting materials, such as polyolefins, polyesters, including
biodegradable polyesters (e.g., polylactides, polycaprolactones,
etc.), polyamides, polyimides, polynitriles, etc.). Further
non-limiting examples of possible materials include, for example
and without limitation, silica, polysiloxanes, silicone materials
which optionally may contain organic and metal residues, and/or the
like. In some embodiments, silica particles are preferred, but not
in all embodiments.
[0114] According to some embodiments, the carrier comprises amino
acids, proteins, salts and minerals and/or similar molecules or
materials, as desired or required.
[0115] In one embodiment, the material, which forms the core
structure of the carrier, is manufactured or otherwise obtained
using one or more of the following: 3D printing, microfluidics,
sol-gel methods (e.g., bottom-up methods or top-down methods of
fabrication), genetically engineered organism producing specific
proteins or amino acids that can either self-assembly such as
ferritin protein particles or conjugate to larger entities any
other method or technique, and/or combinations thereof.
[0116] In one embodiment, the core material comprises one or more
materials, such as, for example, mesoporous silica nanoparticles
with ordered mesostructures of pores. Such pores can be loaded with
different drugs. The most common methods for drug loading to
particles is either by physical adsorption using a highly saturated
drug solution (e.g., a hydrophobic solvent such as cyclohexane with
a hydrophobic drug) or an aqueous solution for water-soluble drugs.
In some embodiments, loading further includes covalently
conjugating the molecule to the particle surface using, for
example, thiol chemistry and/or attracting the cargo molecule by
having a different charge than the particle (e.g., particles having
a positive charge which will allow loading of negatively charged
drug, RNA/DNA molecules).
[0117] The carriers (e.g., particles or objects) disclosed herein
can be synthetized in various sizes and shapes. In one embodiment,
the material forming the core of the carrier contains pores with
diameters between 1 and 75 nm, such as, for example, 2 to 50 nm,
2.5 to 30 nm, 2 to 5.5 nm, other values or ranges within the
foregoing. In some embodiments, determining the hydrodynamic size
using dynamic light scattering (DLS) makes it possible to confirm
redispersibility of particle. In some arrangements, the morphology
and particle diameter can be measured by either scanning electron
microscope (SEM) or transmission electron microscopy (TEM). In
order to determine surface area, pore size and pore volume,
N2-sorption measurements can be used. The size and volume of the of
the mesopores can be detected using small angle X-ray (SAXRD),
according to some embodiments. The drug loading is, in some
embodiments, measured by Thermogravimetric analysis (TGA) and
alternatively or additionally measured by UV/vis spectroscopy
measurements at a wavelength of 425 nm. Any alternative method or
technology of forming the carriers and/or determining measurements
can be used, either in addition to or in lieu of those disclosed
herein, as desired or required.
[0118] In one embodiment, the core material comprises mesoporous
silica nanoparticles (MSNs).
[0119] In one embodiment, the material compromises a nanoparticle
core with coated targeting ligands with a possibility of (or
configured to allow for) loading the particle with API, drugs,
molecules, proteins and amino acids, RNA or DNA and compounds of
interest.
[0120] In one embodiment, the material compromises a nanoparticle
core and/or microparticle core with coated and/or functionalized
targeting ligands with a possibility of (or configured to allow
for) loading the particle into or onto with API, drugs, molecules,
proteins and amino acids, RNA or DNA and compounds of interest.
[0121] Thus, in one embodiment, an nano and/or micro sized particle
for example solid lipid particle (e.g., palmitate-based or
stearylamine and the matrix lipid Compritol) having a net positive
charge can be decorated/coated with negative molecules, such as RNA
or DNA encoding for example interferon gamma for targeted
delivery.
[0122] Thus, in one embodiment, the nanomaterial compromises a core
particle or object functionalized with targeting moieties, drugs,
amino acids, protein or any combination thereof, such as hybrid
materials containing but not limited to
1,2-Dioleoyl-3-trimethylammonium propane (DOTAP), Cholesterol
(Chol), Dioleoylphosphatidylethanolamine (DOPE) and/or
1,2-Distearoyl-sn-glycero-3-phosphorylethanolamine (DSPE),
polyethylene glycol (PEG) (e.g. DOTAP:Chol:DOPE:PEG or
DOTAP:Chol:DSPE:PEG) loaded with, for example and without
limitation, RNA and/or DNA. In some embodiments, the object is
preferably loaded with an active substance, drug or API.
[0123] In some embodiments of the present application and the
technologies disclosed herein, two ways of synthetizing
nanomaterials or other carriers are in particular employed. These
include the top-down and the bottom-up approach or hybrid approach
where some of the particle components are done with one approach
and another component with another approach. In other embodiments,
however, carriers can be synthesized or otherwise manufactured
using other methods or approaches, as desired or required.
[0124] In the top-down approach, for example, the building
materials have larger dimensions than the final product, which
means that the materials undergo physical stresses, such as, e.g.,
grinding, milling etc., in order to be reduced in size. This
process can lead to surface imperfections that could give rise to
some variations in the final product that affect particle
distribution in the host and binding kinetics.
[0125] In some embodiments, the bottom-up method starts by using
smaller building blocks in solution transforming gradually to the
final product, which can provide a more cost-efficient way of
producing nanomaterials and/or micromaterials. Common bottom-up
methods include, for example, co-precipitation, template synthesis
and sol-gel method where the building blocks are often copolymers,
colloids and liquid crystals and self-assembling components such as
ferritin protein particles.
[0126] The carrier or particle system comprising of a core and
functionalization can be characterized, in some arrangements, using
Scanning electron microscopy and/or electron microscopy to confirm
the size, monodispersity, morphology and non-agglomerated state of
the particles. In some embodiments, to find (e.g., accurately,
approximately) the amount of drug loading in the particle if the
drug is fluorescent, particles can be dispersed in ethanol for
complete drug elution. The concentration of drug can be determined
by UV/vis spectroscopy measurements at a wavelength of 425 nm, for
example with Celastrol. In some embodiments, from such
measurements, the drug loading amount can be calculated or
approximated. The mesoscopic ordering of the particles can be
detected by powder-XRD using a Kratky compact small-angle system or
similar X-ray diffraction (XRD) methods. In some embodiments, the
hydrodynamic size of the particles can be determined by dynamic
light scattering, and the mesoporosity by nitrogen sorption
measurements. Thermogravimetric analysis can be used in order to
estimate the amount of PEI, sugar motifs, FA or MTX or other
organic content functionalized to the particle. In some
embodiments, thermogravimetric analysis can be used to estimate the
amount of organic contact or other molecule and/or drug content
functionalized to the particle.
[0127] In one embodiment, inhibiting the spread of the virus
SARS-CoV-2, influenza, rhinovirus, other viruses causing
respiratory infection and/or any other virus includes using a
carrier (e.g., a mesoporous silica nanoparticle, lipid
nanoparticle, protein-based nanoparticle or any combination thereof
with similar size as the virus). In some embodiments, such
nanoparticles or other carriers are configured to be strategically
provided or otherwise administered to a host in one or more ways
(e.g., via inhalation, oral ingestion, intravenous injection,
topical application, etc.), as desired or required. In some
arrangements, the carriers (e.g., nanoparticles) include a size of
1 to 200 nm (e.g., 1 to 200, 10 to 120, 50 to 100, 90 to 110, 100
nm, values between the foregoing ranges, etc.). In some
embodiments, the carriers include a size of 0.01 to 1000 nm (e.g.,
0.01 to 1000, 10 to 1000, 50 to 1000, 100 to 1000, 1 to 500, 500 to
1000, 200 to 800, 400 to 600 nm, values between the foregoing
ranges, etc.). In some embodiments, the carriers include a size of
0.2 to 100 nm (e.g., 0.2 to 100, 1 to 10, 2 to 20, 5 to 50, 10 to
100 nm, values between the foregoing ranges, etc.). Further, the
nanoparticles can be fabricated using the bottom-up sol-gel method
or top-down method.
[0128] In some embodiments, by using known viral genetic
information, such as known viral (e.g., coronaviral, influenza
viral, rhinoviral and/or other viral, etc.) genetic information, it
is possible to produce similar peptides present in targeted
viruses. For example, peptides or other structures can be similar
or substantially similar to those found in viral glycoprotein
spikes and/or protein protrusions, thus, in some arrangements,
mimicking (e.g., at least substantially or approximately) at least
some of the viral surface properties that assist with the binding
of the carrier to certain receptors (e.g., ACE2 N-terminal helix or
sialic acid, histo-blood group antigens, ICAM-1, IGF1R, other
target receptors ACE2, etc.). In some arrangements, the carrier can
include amino acid sequences found in the viral receptor binding
domain (RBD) or the viral receptor binding motif (RBM) in the S
protein, HA or NA or VP other decorated proteins that could be used
or functionalizing the particle with similar (e.g., substantially
similar) or identical peptides. Alternatively or additionally, the
carrier's ability to at least partially inhibit entry of viruses
can be enhanced by including organic polymers as part of the
protrusion (e.g., of cationic polyamidoamine dendrimer (PAMAM)) or
by predicting an amino acid sequence or polymer for producing a
surface coating which is similar in surface charge as the viral
surface or by attaching targeting motifs which are known to bind to
the target receptor allowing selective internalization in target
cells [6-9,20].
[0129] In one embodiment, the carriers disclosed in the present
application or variations thereof comprise mesoporous silica
particles. In some embodiments, such carriers preferably include a
spherical or substantially spherical form or shape. In some
arrangements, the particles or other carriers are provided with a
plurality of protruding (e.g., relative to a spherical or
substantially spherical core) peptide structures in the form of
protein spikes or protein fragments/protrusions on their surfaces.
In some embodiments, each of the particles include 5 to 500
protruding peptide structures (e.g., 5 to 500, 0 to 100, 100 to
200, 200 to 300, 300 to 400, 400 to 500, 100 to 500, 200 to 500,
300 to 500, 0 to 200, 0 to 300, 0 to 400, 0 to 500, values between
the foregoing ranges and values, etc.). In some embodiments, each
of the particles include 1 to 1000 protruding peptide structures
(e.g., 1 to 1000, 0 to 100, 100 to 200, 200 to 300, 300 to 400, 400
to 500, 100 to 500, 200 to 500, 300 to 500, 100 to 600, 200 to 600,
300 to 600, 400 to 600, 500 to 600, 100 to 700, 200 to 700, 300 to
700, 400 to 700, 500 to 700, 600 to 700, 100 to 800, 200 to 800,
300 to 800, 400 to 800, 500 to 800, 600 to 800, 700 to 800, 100 to
900, 200 to 900, 300 to 900, 400 to 900, 500 to 900, 600 to 900,
700 to 900, 800 to 900, 100 to 1000, 200 to 1000, 300 to 1000, 400
to 1000, 500 to 1000, 600 to 1000, 700 to 1000, 800 to 1000, 900 to
1000, 0 to 200, 0 to 300, 0 to 400, 0 to 500, 0 to 600, 0 to 700, 0
to 800, 0 to 900, 0 to 1000, values between the foregoing ranges
and values, etc.).
[0130] In one embodiment, the surface features or other members
that protrude from a core of the carrier (e.g., spikes) have a
length of about 1 to 200 nm (e.g., 1 to 200, 1 to 100, 2 to 80, 5
to 50, 20 to 100, 50 to 100, 100 to 200 nm, values between the
foregoing, etc.). In some embodiments, the surface features or
other members that protrude from a core of the carrier (e.g.,
spikes) have a length of 0.2 to 100 nm (e.g., 0.2 to 100, 1 to 10,
2 to 20, 5 to 50, 10 to 100 nm, values between the foregoing
ranges, etc.). In some embodiments, the length includes the actual
length of a spike or other protrusion is the total liner length of
such a spike or protrusion. However, in other embodiments, the
length includes the distance from the spherical or other core of
the carrier to the outermost radial distance of the protrusion.
[0131] In some embodiments, allowing the carrier (e.g., synthetic
particle) to compete with viral particles, such as coronaviruses
(e.g., the SARS-CoV-2 virus, variants thereof, etc.), influenzas,
rhinoviruses, Respiratory Syncytial Viruses (RSVs), noroviruses,
other viruses, etc.) for the same receptor and/or other binding
site or portion of a host cell (e.g., ACE2, sialic acid,
histo-blood group antigens, ICAM-1, IGF1R receptor, etc.) can
function as a hindrance and/or other obstacle (e.g., allosteric
regulation or hinder, other competitive or non-competitive
inhibition, etc.) for the viral particle to bind to the receptor or
other site or portion. This can advantageously minimize or reduce
the likelihood of endocytosis of the virus or other pathogen,
thereby lowering the risk of infecting the host cell.
[0132] One embodiment of the principle of competitive inhibition is
schematically illustrated in FIG. 2. As shown, by way of an
example, in some embodiments, a host receptor (e.g., ACE2) is
responsible for mediating the SARS-CoV-2 infection responsible for
coronavirus disease 19 (e.g., COVID-19). In some configurations, by
binding carriers (e.g., the novel synthetic nanoparticles, other
particles, objects, etc.) to that reception site (e.g., receptor),
to the specific host receptors motifs and/or other any other site
or portions of the host cell, infection (e.g., caused by the
SARS-CoV-2 viruses, other viruses, etc.) can be advantageously
prevented, controlled and/or otherwise mitigated.
[0133] With continued reference to FIG. 2, by way of an example, a
host receptor (e.g., ACE2) responsible for mediating the infection
resulting in a specific disease is generally depicted
(schematically). In some embodiments, by binding a carrier (e.g., a
novel synthetic particle, object, etc.) to that specific area or to
the specific host receptors motifs, the infection caused by the
specific virus, viruses and/or other pathogen can be prevented and
controlled (e.g., the likelihood of infection can be reduced or
otherwise mitigated, etc.). The competitive inhibition can be
utilized against different viruses and/or other pathogens (such as,
for example and without limitation, influenzas, rhinoviruses, RSVs,
noroviruses, other respiratory and gastrointestinal viruses, other
viruses or pathogens, etc.).
[0134] Based on, for example, the foregoing, in an embodiment,
carriers (e.g., synthetic nanoparticles, other particles, etc.) are
selected such that they resemble, at least partially, coronaviruses
(e.g., SARS-CoV-2), influenzas, rhinoviruses, noroviruses, other
common cold viruses and/or any other viruses or pathogens, as
desired or required. In some embodiments, preferably, synthetic
nanoparticles are enhanced or otherwise optimized, at least
partially, for competitive inhibition. For example, the particle
morphology, size, surface properties and/or any other properties or
features of such particles can be modified to achieve higher (or
otherwise improve) affinity for the target receptor angiotensin
converting enzyme 2 (ACE2) and/or TMPRSS2, sialic acid, histo-blood
group antigens, ICAM-1, IGF1R or other target receptors. Thus, the
binding affinity for the specific receptor can be advantageously
increased, thereby blocking the internalization of the viral
envelope more efficiently and potentially prolonging the gained
viral protection [8-10].
[0135] A carrier system as described herein, wherein the carrier
(e.g., synthetic nanoparticle, other particle or object, etc.)
resembling a targeted virus (e.g., the SARS-CoV-2, other corona or
spiked viruses, influenza, rhinoviruses, noroviruses, other common
cold viruses, etc.) can be enhanced or optimized for personalized
medicine as variations and mutations in individuals might give rise
to slightly different target receptors. Thus, the surface
properties and functionalization of the carrier can be changed to
match or substantially match the individual properties (e.g.,
mutations or variations) in target receptors and/or other binding
sites or locations of a host cell for tailored therapies.
[0136] One embodiment of a targeted and/or personalized medicine is
schematically illustrated in FIG. 4. As depicted, by way of an
example, by designing a carrier (e.g., synthetic nanoparticle,
other particle or object, etc.) that has features that resemble the
selected or targeted virus or other pathogen (e.g., SARS-CoV-2,
other corona or spiked viruses, influenzas, rhinoviruses,
noroviruses, other common cold viruses, etc.). For example, the
synthetic particles or other carriers can include spike protein
fragments, protein protrusions, other protrusions, other surface
features and/or any other feature or property. Accordingly, it is
possible for targeted drug delivery at (e.g., at, to, near, etc.)
host cells that are susceptible for the virus and/or other
pathogen. In some embodiments, as discussed herein, the carrier can
include (e.g., can be "loaded" or otherwise provided with) one or
more drugs and/or other compounds, substances and/or materials (for
example, anti-viral compounds, zinc, immune modulating drugs (e.g.,
Celastrol, other interferon-gamma or stimulating molecules,
penicillium, Dalbavancin or other anti-bacterial compounds, drugs
intended to combat virus-related pneumonia, voriconazole,
isavuconazole, drugs intended to combat viral-associated pulmonary
aspergillosis, anti-fungal compounds, etc.) and/or the like, as
desired or required by a particular application or use.
[0137] In some embodiments, the synthetic particle or other carrier
comprises (e.g., is provided with) a coating and/or
functionalization that has higher affinity towards the receptor
favoring the binding of the synthetic particle or other carrier
than the viral one (e.g., the virus, other pathogenic or infectious
agent or member, etc.).
[0138] In one embodiment, for example, the synthetic particle or
other carrier comprises an amino acid sequence that is similar to
that of the said viral protrusion having affinity for the same
target receptor as the pathogen thus having competition for the
same receptor.
[0139] In one embodiment, for example, the synthetic particle or
other carrier is further optimized for improved binding to said
host receptor in order to achieve improved blocking effect by
competitive inhibition to the said pathogen.
[0140] In one embodiment, for example, the synthetic particle or
other carrier having coating and/or functionalization of epitopes
similar to that of the pathogen of interest in order to give a
vaccination at target cell population.
[0141] In one embodiment, for example, silica (e.g., stable organic
silica) is used as the core material that could exhibit a blocking
effect that, optionally after modification of the particle, could
be prolonged for hours, days or longer as it takes time for silica
nanoparticles to degrade in aqueous conditions similar to the
environment of the human body.
[0142] In one embodiment, for example, solid lipid particles (e.g.,
fabricated by a bottom-up method using microfluidics) are used as
the core material for the carrier to be further coated,
functionalized and/or loaded into or onto with API, epitopes,
proteins, RNA/DNA, anti-virals and immune stimulating compounds
such as Celastrol, interferon gamma.
[0143] In one embodiment, for example, self-assembling protein
particles produced by genetically-engineered bacterial or mammalian
cells producing proteins or protein fragments, such as ferritin
heavy or light chain, are used as the core material for the
carrier. Such particles can be further functionalized and/or loaded
into or onto with other molecules, epitopes, API, epitopes,
proteins, RNA/DNA, anti-virals and immune stimulating compounds
such as Celastrol, interferon gamma.
[0144] According to some embodiments, the administration route of a
carrier depends on the tissue that the virus has invaded. For
example, if the virus or other targeted pathogen resides in the
upper or lower respiratory tract, it may be preferred to use an
inhalation device for administering the carriers (e.g., synthetic
particles) with a desired dosage. In some arrangements, such an
inhalation device can allow a desired (e.g., optimal, effective,
etc.) dosage of a carrier to be provided to a targeted anatomical
location on demand.
[0145] In one embodiment, there is provided an inhalation device
which compromises a container (e.g., a small plastic container)
with dried carriers (e.g., synthetic particles, objects, etc.) like
that of a dry powder inhaler or as a meter dose inhaler where the
carriers (e.g., particles) are sprayed from the inhaler as an
aerosol, as an vaporizer creating a fine mist of particles and
solution, as an nasal spray dispersed in an aqueous solution and/or
in any other form or configuration or hybrid form, as desired or
required.
[0146] In some embodiments, for improving or enhancing (e.g.,
maximizing) the coverage of the upper respiratory tract, an
inhalation mask is used. As a result, the entry of carriers (e.g.,
particles) into the nasal cavity and lower respiratory tract (where
epithelial cells expressing ACE2, sialic acid, histo-blood group
antigens, ICAM-1, IGF1R or other receptors that may also reside)
can be enhanced or otherwise improved, thereby lowering (e.g.,
minimizing) the risk of being infected by the virus or other
pathogen, at least temporarily.
[0147] In embodiments where the viral infection is (or would be) in
the gastrointestinal tract, a tablet, an orally ingestible liquid
and/or any other ingestible material is the preferred route of
administration of the carrier to the host or subject. The synthetic
particles or other carriers of such orally administered
compositions can advantageously temporarily protect, at least
partially, the end-user from infection by the virus (e.g., orally,
via fecal-oral transmission, etc.).
[0148] The carrier (e.g., nanomaterial, other particle or object,
etc.) can also be fabricated and configured to have a high or a
favorable affinity for the pathogen, thus, at least partially,
encapsulating and immobilizing the threat of infection e.g. coating
or functionalizing the particle with molecules that has high
binding affinity towards the pathogen. Accordingly, such carriers
could be used in disinfecting products (e.g., cleaning solution,
hand sanitizer products, disinfecting wipes, etc.).
[0149] FIG. 3 shows, schematically and by way of an example,
utilization of carriers (e.g., nanoparticles, other particles or
objects, etc.) coated and/or otherwise provided with peptides
resembling the binding motif of the target receptor, such as, e.g.
ACE-2, sialic acid, histo-blood group antigens, ICAM-1, IGF1R or
other receptors that the specific or targeted virus or other
pathogen uses. For example, such targeted viruses or other
pathogens include, without limitation or restrictions,
coronaviruses (e.g., SARS-CoV-2), influenzas, rhinoviruses,
noroviruses and other common cold viruses and/or the like. In some
embodiments, as discussed throughout this application, the carriers
are configured to encapsulate and/or immobilize the virus and/or
other pathogen, thus minimizing or otherwise reducing the risk of
the virus and/or other pathogen infecting the host.
[0150] The carrier (e.g., nanomaterial, other particle or object,
etc.) can also be fabricated to have high or favorable affinity
both for the pathogen. Thus, the carrier can be configured to
encapsulate and immobilize the targeted virus or other pathogen.
Further, as noted herein, the synthetic particle or other carrier
can be provided with a coating or similar layering or component
that has higher or otherwise favorable or improved affinity towards
the receptor favoring the binding of the carrier (e.g., synthetic
particle) relative to the affinity of the virus or other pathogen,
thereby, allowing the carrier to be used in a dual targeting
approach (e.g., further reducing (e.g., minimizing) the risk of
contracting said disease (e.g., viral or pathogenic infection and
the diseases originating therefrom).
[0151] FIG. 4 schematically shows, by way of an example only,
utilization of nanoparticles or other carriers coated (or otherwise
provided) with peptides resembling the binding motif of a viral
protrusion protein, such as, for example, the spike protein from
the SARS-CoV-2 or other coronaviruses, Hemagglutinin (HA) and
Neuraminidase (NA) proteins from influenza A virus, etc. combined
with peptides resembling the binding motif of host receptors (e.g.,
ACE2, sialic acid, histo-blood group antigens, ICAM-1, IGF1R or
other receptors) of the subject. As a result, the carriers can
advantageously be provided with dual targeting strategies, thereby
minimizing or reducing the risk of viruses or other pathogens
infecting the host.
[0152] According to some embodiments, the carrier (e.g.,
nanomaterial, particle or object, etc.) can be fabricated or
otherwise configured to have high or favorable affinity for the
targeted pathogen(s) (e.g., virus(es)) circulating co-receptors
e.g. high-density lipoprotein (HDL) scavenger receptor B type 1
(SR-B1), thus immobilizing the treat which could be used as an
antidote preventing further spreading of the virus in the said
host.
[0153] FIG. 5 schematically shows, by way of an example only,
utilization of nanoparticles or other carriers coated (and/or
otherwise provided) with peptides resembling the binding motif of
the spike protein from a coronavirus (e.g., the SARS-CoV-2 virus)
for at least partially encapsulating and immobilizing the
co-receptor. As a consequence, the mobility of the virus can be
advantageously decreased, thus minimizing or otherwise reducing the
risk of the targeted virus or other pathogen infecting the host or
spreading the viral infection inside the said host to other
organs.
[0154] Based on, for example, the above, the following represents
non-limiting embodiments of the present technology:
[0155] A carrier (e.g., synthetized carrier in the nano- or
microscale or any other object that has the capacity of saturating
and binding to target receptors, proteins and/or macromolecules for
example but not limited to ACE2, sialic acid, histo-blood group
antigens, ICAM-1, IGF1R or other receptors at the surface of cells
that prevents and minimize pathogen, such as influenzas,
rhinoviruses, RSVs, noroviruses, coronaviruses (e.g., SARS-CoV-2),
other viruses causing respiratory infection, binding and entry to
the host lowering the risk of contracting the specific disease,
such as COVID-19 disease, diarrhea, common cold, cytokine storm,
death or generally discomfort or a combination thereof.
[0156] A carrier (e.g., a synthetized carrier in the nano- or
microscale or any other object that has the capacity of binding and
encapsulating the pathogen of interest, thus immobilizing, at least
partially, the pathogens ability to bind and entry to the host,
thereby lowering the risk of contracting the specific infectious
agent).
[0157] A carrier (e.g., a carrier as above), wherein the core
structure of the carrier is obtained (e.g., manufactured,
fabricated, etc.), at least in part, by 3D printing, microfluidics,
supercritical solution method, sol-gel method, other bottom-up
and/or top-down method of fabrication self-assembling components
and/or any other method or technology.
[0158] A carrier (e.g., as provided above and/or herein), where the
core material is made of or comprises, however not limited to,
organic or inorganic components, lipid droplets, micelles,
cholesterol, amino acids, proteins, salts and minerals or other
molecules.
[0159] One embodiment comprises lipid-based micelles made by, for
example, cholesterol decorated with SARS-CoV-2 spike protein
fragments and/or other protrusions that bind both to host receptor
sites or other portions of the host cell (e.g., ACE2, TMPRSS2,
etc.) and to cholesterol and its high-density lipoprotein (HDL)
scavenger receptor B type 1 (SR-B1) that would facilitate
ACE2-dependent entry of the nanoparticle and/or microparticle
loaded with selected API for combating COVID-19 disease or other
disease resulting from infection by a virus or other pathogen. In
some embodiments, the cholesterol recognition amino acid consensus
(CRAC) motifs near the inverted cholesterol recognition motif
(CARC) have been proven to bind with SARS-CoV-2 S1 subunit and this
HDL complex enhances viral entry to host cells facilitating
replication [17]. Therefore, by creating a carrier (e.g.,
nanoparticle, other particle or object, etc.) that would compete
with this spike protein-HDL interaction would potentially lower the
ability of SARS-CoV-2 (or the targeted pathogen for ACE2-mediated
(or other receptor-mediated) internalization, at least partially
blocking viral entry to host cells and at least partially hindering
replication. In one arrangements, this co-receptor incarceration
could be blocked by decorating the nanoparticle with spike protein
fragments from CARC-CRAC region of SARS-CoV-2 preferably but not
limited to 129KKKKVCEFQFCNDPFLGVYYHKNNKKKK150 (SEQ ID No: 4)
together with other amino acids for example the RBD spike fragment
hexapeptide 438YKYRYL443 (SEQ ID No: 1) that binds to the ACE2
receptor creating a nanoparticle capable of blocking viral-host
interaction on multiple positions loaded with selected API for
targeted therapeutics (e.g., Celastrol, Zinc, ITX 5601, etc.).
[8,15-18].
[0160] One embodiment comprises the use of simultaneous inhibiting
and immobilizing by dual targeting approaches, where the carrier
(e.g., mimetic particle) has protrusions on the outer surface that
are similar to those of the virus, for example, spike protein, HA
and NA or VP that would bind to the specific host receptor for
inhibiting viral entry by competitive inhibition. In some
embodiments, the carrier (e.g., virus-like particle) also includes
surface protrusions that mimic the host component (e.g., ACE2,
silicid sialic acid, histo-blood group antigens, ICAM-1, IGF1R
receptors, and/or antibodies such as the monoclonal antibody
bebtelovimab, etc.).
[0161] Another embodiment comprises using self-assembling
recombinant protein-based nanoparticle constructs, such as, for
example, SpyTag/SpyCatcher system and ferritin-based constructs
[23]. Where the constructs are expressed in E. Coli; the proteins
are purified and then assembled like a two-component "superglue"
into virus-like particles (VLPs) conjugated with the selected
antigens, viral epitopes or fragments [24]. The carrier could be
assembled using the SpyTag/SpyCatcher system or ferrtin (heavy or
light chain) based particle core and then conjugated, coated and/or
functionalized with the selected SARS-CoV-2 spike protein or
selected hexapeptide 438YKYRYL443 derived thereof or peptides from
the CARC-CRAC region or other proteins of interest. Several studies
show that it is possible to construct such a VLP using SARS-CoV-2
spike protein (RBD) candidate combined with SpyCatcher technology
and ferritin based particle systems [24, 25]. The selected studies
using RBD-SpyVLP demonstrate that the construct is easily
producible and scalable, and that the final product is thermally
stable even at room temperature for several weeks [25]. The
SARS-CoV-2 RBD conjugated to SpyCatcher-mi3 nanoparticle
(abbreviated: RBD-mi3 NP) shows higher binding affinity for the
ACE2 receptor than viral RBD monomers detected using Biolayer
interferometry (BLI) kinetic assays [24]. Therefore, it appears
possible to develop mimetic nanoparticles or other carriers for
preventing the spreading and lowering the infection rate of novel
coronaviruses with higher affinity then the RBD monomer.
[0162] The synthetic carrier or nanoparticle may comprise or be
decorated with a polypeptide or protein having an amino acid
sequence of the ACE2 binding sequence and/or the SARS-CoV-2 spike
protein RBD or a fragment thereof. In an embodiment, the amino acid
sequence of the ACE2 binding sequence and/or the SARS-CoV-2 spike
protein RBD or a fragment thereof is optimized, for example such
that it has a higher binding affinity for the ACE2 receptor and
enhanced blocking properties that of the spike protein of the
coronavirus interaction compared to the corresponding, unmodified
spike protein sequence (SEQ ID No: 5). By optimizing the amino acid
sequence of the ACE2 binding sequence and/or the SARS-CoV-2 spike
protein RBD or a fragment thereof it is possible achieve even
higher binding affinity for example with combining hexapeptides
438YKYRYL443 (SEQ ID No: 1) or 438YKYNYL443 (SEQ ID No: 3) with the
optimized spike protein sequence.
[0163] In a carrier as above, according to some embodiments, the
core or core material may be made of, for example, self-assembling
virus-like protein nanoparticles that can be saturated with
different drugs. These particles can be synthesized in various
sizes and shapes.
[0164] A carrier as above, where the core material is made of, for
example, mesoporous silica nanoparticles with ordered
mesostructures of pores that can be loaded with different drugs and
that these particles can be synthetized in various sizes and
shapes.
[0165] A carrier as above, wherein the core material is
functionalized with one or several of the following: peptides or
proteins such as antibodies, chemical agents, active pharmaceutical
ingredients (API), organic or inorganic polymers or molecules.
[0166] A functionalized carrier as above, wherein the carrier with
its functionalization provides a method of specifically bind to
receptors, proteins and macromolecules at the cellular level in
order to prevent and minimize pathogen entry to the host target
tissues by competitive inhibition.
[0167] A functionalized carrier as above, wherein the carrier with
its functionalization provides a method of specifically bind to
receptors, proteins and macromolecules at the cellular level in
order to prevent and minimize SARS-CoV-2, influenzas, rhinoviruses,
respiratory syncytial virus, norovirus and other viruses causing
respiratory infection entry to the host target receptors by
competitive inhibition.
[0168] A carrier system as above, wherein the carrier with its
functionalization provides a method of loading drugs, API,
molecules, peptides inside or onto the carrier system.
[0169] A carrier system as above, where the functionalized and drug
loaded carrier system can be used for targeted drug delivery of
anti-pathogenic, anti-viral or anti-microbial compounds in order to
decrease the growth of the infectious agent.
[0170] A carrier system as above, where the functionalized and drug
loaded carrier system can be used for targeted drug delivery of,
anti-viral compounds in order to decrease the replication rate of
the coronavirus.
[0171] A carrier system as above, wherein the synthetic
nanoparticle resembling the SARS-CoV-2 virus is loaded into or onto
the nanoparticle for further enchanting the anti-viral properties
of the invention. For example, Zinc which has been shown to reduce
viral replication in its host cells, can be employed [21]. Also,
viscosity modulators, antihistamines, Celastrol and/or
immunosuppressors can be used in the COVID-19 disease for
minimizing the cytokine storm that potentially is dangerous to some
patients [18,21,22].
[0172] A carrier system as above, wherein the synthetic
nanoparticle resembling the SARS-CoV-2, influenzas, rhinoviruses
and other viruses causing respiratory infection is loaded with
proteome inhibitors or new molecular entities developed in the
future for efficiently deliver the compounds in the target tissues
with minimal off-target effects.
[0173] A carrier system as above, wherein the synthetic
nanoparticle is decorated with molecules that has high affinity
towards the SARS-CoV-2 virus or influenzas, rhinoviruses and
viruses causing respiratory infection e.g. proteins resembling that
of the ACE-2, sialic acid, histo-blood group antigens, ICAM-1,
IGF1R receptor or any other pathogen of interest in order to bind
and immobilize the infectious agent preventing or minimizing the
potential risk of host entry.
[0174] A carrier system as above, wherein the synthetic
nanoparticle resembling the SARS-CoV-2 virus, or any other pathogen
for example influenzas, rhinoviruses and viruses causing
respiratory infection is decorated with epitopes to be used as a
vaccination at target cell populations.
[0175] A carrier system as above, wherein the carrier system is
loaded, stored or dispersed in a device or vessel capable of
on-demand release of the carrier to the end-user.
[0176] A carrier system as above, wherein the carrier system is
loaded inside a dispenser such as an inhalation device, tablet,
injectable substance, cream or ointment.
[0177] A carrier system as above, wherein the man-made materials
are used to immobilize specific pathogens by adding the synthetic
material in sanitation products and disinfectants.
[0178] A carrier system as above for minimizing the spread of
diverse pathogens by binding to the target molecule in the hos body
or binding to the infectious agent itself and potently inhibit the
spread of the disease. Furthermore, as a combination treatment
listen in the preceding embodiments hindering the replication of
the infectious agent together with giving the immune system in the
host a gained advantage to fight the disease similar to vaccines or
immunoregulating drugs.
[0179] In further embodiments, the present invention is thus
directed to a method for preparing a synthetic nanomaterial
comprising a core object, particle, sheet, film or spheroid,
tringle, star shaped, said object also compromising a coating or
functionalization of organic polymers, amino acids proteins or
molecules mimicking the surface of the pathogen, such as the
coronavirus of interest, i.e. SARS-CoV-2 and future variants
alternatively influenzas, rhinoviruses and other viruses causing
respiratory infection. FIG. 7 exemplifies how the SARS-CoV-2 spike
protein, and variation thereof, may be produced using a vector for
producing the specific protein construct to be conjugated to the
virus-like nanoparticle or synthetic carrier.
[0180] Producing a man-made material that has the capability of
mimicking the pathogen of interest that has the capability of
competing with the pathogen of interest for the same host target
molecule, receptor, amino acid or nucleotide. Alternatively,
producing a material that has the capability of binding and
immobilizing the pathogen of interest minimizing the possible
infection in its host.
[0181] Producing a man-made material that has the capability of
mimicking the coronavirus of interest i.e., SARS-CoV-2 or
influenzas, rhinoviruses and other viruses causing respiratory
infection that has the capability of competing with the virus for
the same host target molecule, receptor, amino acid or nucleotide
e.g., ACE2 and/or TMPRSS2, sialic acid, histo-blood group antigens,
ICAM-1, IGF1R receptors.
[0182] One embodiment comprises the steps of:
[0183] a) providing a core material, e.g. a nano- and/or
micro-material including nanoparticles, microparticles or any other
object as disclosed herein;
[0184] b) coating or functionalizing the core material with
molecules, polymers, amino acids, proteins, API, drugs or other
material as disclosed herein;
[0185] c) loading the object with compounds, molecules, drugs, API,
DNA or RNA etc.;
[0186] d) coating a second protective or functional layer on top of
the object in particular for increasing its resistance that could
be important in extreme environments such as the acidic environment
in the stomach; and
[0187] e) providing a small device, medical device, inhalation
device or aerosol, sanitation product or consumer product that
on-demand will release the containing synthetic material, particle
or object for administration.
[0188] FIG. 7 shows an example of a SARS-CoV-2 spike RBD
(receptor-binding domain) expression construct. Different
expression cassettes (shown as the XXX region) can be used for
expressing the desired construct e.g. influenza H7 haemagglutinin
(indicated as "Signal sequence"), Tag, spacer, and SARS-CoV-2 RBD
(using amino acid region 319 to 541, depicted in SEQ ID No: 5;
PUBMED 32015508 [26]; the full amino acid sequence of the surface
glycoprotein of SARS-CoV-2 is shown in in SEQ ID No: 6). The spike
protein construct can be further optimized for ACE2 receptor
interaction using other known amino acid sequences from SARS-CoV-2
variants such as but not limited to Alpha (B.1.1.7), Beta
(B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron (B.1.1.529)
and/or predicted amino acids or amino acid substitutions e.g. V367F
[27], W436R, and/or N354D/D364Y.
[0189] FIG. 7 exemplifies how a spike protein, and variation
thereof, or other viral protein, may be produced using a vector for
producing the specific protein construct to be conjugated to the
virus-like nanoparticle or synthetic man-made carrier. In an
embodiment, the synthetic carrier or synthetic nanoparticle
comprises and/or is coated with a peptide, a polypeptide or a
protein having an amino acid sequence comprising (or consisting of)
a sequence as set forth in any one of SEQ ID No:s 1, 2, 3, 4, 5
and/or 6. In a further embodiment, the synthetic carrier or
synthetic nanoparticle comprises and/or is coated with a
polypeptide or a protein having an amino acid sequence comprising
(or consisting of) a sequence as set forth in SEQ ID No. 5 and/or
6, wherein the sequence optionally comprises one or more amino acid
substitutions. The one or more amino acid substitutions may be
selected from (but are not limited to) V367F, W436R, and/or
N354D/D364Y or other amino acid substitutes consisting of new
coronavirus variants of concern (VOC) having higher affinity for
the target receptor (table 1). To be used against contracting the
COVID-19 disease and to release and shorten the disease progression
and duration.
[0190] The following represent non-limiting embodiments of the
present technology. The following is a non-exclusive list of
embodiments, and as such, should not be seen to limit, in any way,
the various inventions disclosed herein.
[0191] 1. A method of preventing or reducing pathogen binding to
target areas of cell surfaces of a host selected from mammals,
comprising providing administering to the mammal a carrier
comprising biocompatible particles having a maximum size in at
least one dimension in the nanometer or micrometer range, forming a
core, and further having a functionalized surface capable of
binding to said target areas of said cell surfaces to at least
temporarily block said target areas to prevent or minimize pathogen
binding and thus, reducing the risk of the host contracting a
disease caused by said pathogen.
[0192] 2. The method according to embodiment 1, wherein the carrier
has the capacity of binding and encapsulating the pathogen, thus
immobilizing the pathogens ability to bind and entry to the host
lowering the risk of contracting the specific infectious agent.
[0193] 3. The method according to embodiment 1 or 2, wherein the
core structure of the carrier is being obtained by 3D printing,
microfluidics, sol-gel method or other bottom-up and/or top-down
method of fabrication.
[0194] 4. The method according to any of embodiments 1 to 3,
wherein the core material comprises organic or inorganic
components, lipid droplets, amino acids, proteins, salts and
minerals or other molecules or wherein the core material comprises
mesoporous silica nanoparticles, in particular mesoporous silica
particles with ordered mesostructures of pores that preferably are
capable of being loaded with drugs.
[0195] 5. The method according to any of embodiments 1 to 4,
wherein the core material is functionalized with substance selected
from the group consisting of peptides, proteins such as antibodies,
chemical agents, active pharmaceutical ingredients (API), organic
or inorganic polymers or molecules and combinations thereof.
[0196] 6. The method according to any of embodiments 1 to 5,
wherein the carrier functionalized for specifically binding to
receptors, proteins and macromolecules at the cellular level in
order to prevent and minimize pathogen entry to the host target
tissues by competitive inhibition.
[0197] 7. The method according to any of embodiments 1 to 6,
wherein the synthetic nanoparticle and/or microparticle is used for
reducing the spread of SARS-CoV-2 virus or other viruses that
causes a respiratory infection, diarrhea, common cold, influenzas
or generally discomfort or a combination thereof.
[0198] 8. The method according to any of embodiments 1 to 7,
wherein said synthetic nanoparticle has a 3D-configuration
generally matching the characteristics of the SARS-CoV-2 virus or
other viruses that causes a respiratory infection, diarrhea, common
cold, influenzas or generally discomfort or a combination thereof,
in particular the particle is fabricated to a size of around 100 nm
and coated with similar amino acids as the glycoprotein spikes or
protruding proteins at the surface of the viral particle or similar
molecules that mimic the surface of the viral envelope.
[0199] 9. The method according to any of embodiments 1 to 8,
wherein said synthetic nanoparticle resembles the SARS-CoV-2 virus,
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses or is optimized for competitive inhibition.
[0200] 10. The method according to any of embodiments 1 to 9,
wherein the synthetic carrier exhibits a modified particle
morphology, size or surface properties to achieve increased
affinity for the target receptor angiotensin converting enzyme 2
(ACE-2), compared with the SARS-CoV-2 virus, and/or other viruses
that causes a respiratory infection, diarrhea, common cold, in
particular for increasing the binding affinity for the specific
receptor e.g; silicid sialic acid, histo-blood group antigens,
ICAM-1, IGF1R blocking the internalization of the viral envelope
more efficiently and potentially prolonging the gained viral
protection.
[0201] 11. The method according to any of embodiments 1 to 10,
wherein said synthetic nanoparticle resembling the SARS-CoV-2
virus, influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is adapted for personalized medicine.
[0202] 12. The method according to any of embodiments 1 to 11,
wherein said the synthetic nanoparticle resembling the SARS-CoV-2
virus, influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is loaded into or onto the nanoparticle for further
enhancing the anti-viral properties.
[0203] 13. The method according to any of embodiments 1 to 12,
wherein said synthetic nanoparticle resembling the SARS-CoV-2
virus, influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is loaded with vehicles or proteome inhibitors for
efficiently delivering the compounds in the target tissues with
minimal off-target effects.
[0204] 14. The method according to any of embodiments 1 to 13,
wherein the synthetic nanoparticle is decorated with molecules that
have high affinity towards the SARS-CoV-2 virus or any other
pathogen of interest such as influenza viruses, rhinoviruses,
common cold viruses and/or noroviruses in order to bind and
immobilize the infectious agent preventing or minimizing the
potential risk of host entry.
[0205] 15. The method according to any of embodiments 1 to 14,
wherein the synthetic nanoparticle resembling the SARS-CoV-2 virus
or any other pathogen such as influenza viruses, rhinoviruses,
common cold viruses and/or noroviruses is coated or decorated with
epitopes to be used as a vaccination at target cell
populations.
[0206] 16. The method according to any of embodiments 1 to 15,
wherein the carrier is loaded, stored or dispersed in a device or
vessel capable of on-demand release of the carrier to the
end-user.
[0207] 17. The method according to any of embodiments 1 to 16,
wherein the carrier system is loaded inside a dispenser such as an
inhalation device, tablet, injectable substance, cream or
ointment.
[0208] 18. The method according to any of embodiments 1 to 17,
wherein the man-made materials is used for immobilizing specific
pathogens by adding the synthetic material in sanitation products
and disinfectants.
[0209] 19. The method according to any of embodiments 1 to 18 for
preventing or reducing pathogen binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said method comprises minimizing the spread of
diverse pathogens by binding to the target molecule in the hos body
or binding to the infectious agent itself and potently inhibit the
spread of the disease.
[0210] The following embodiments are disclosed. The following is a
non-exclusive list of embodiments, and as such, should not be seen
to limit, in any way, the various inventions disclosed herein.
[0211] 1. A synthetic carrier for use in a method of preventing or
reducing pathogen binding to target areas of cell surfaces of a
host, said carrier comprising biocompatible particles having a
maximum size which, in at least one dimension, is in the nanometer
or micrometer range, forming a core, and further having a
functionalized surface capable of binding to said target areas of
said cell surfaces so as to at least temporarily block said target
areas to prevent or minimize pathogen binding and, thus, reducing
the risk of the host contracting a disease caused by said
pathogen.
[0212] 2. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 1, said carrier having the capacity
of binding and encapsulating the pathogen, thus immobilizing the
pathogens ability to bind and entry to the host lowering the risk
of contracting the specific infectious agent.
[0213] 3. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 1 or 2, wherein said core structure
of the carrier is being obtained by 3D printing, microfluidics,
sol-gel method or other bottom-up and/or top-down method of
fabrication.
[0214] 4. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of embodiments 1 to 3, wherein the core
material comprises organic or inorganic components, lipid droplets,
amino acids, proteins, salts and minerals or other molecules.
[0215] 5. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
the core material comprises inorganic silica nanoparticles, in
particular mesoporous silica particles, such particles preferably
having ordered mesostructures of pores that preferably are capable
of being loaded with drugs.
[0216] 6. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said core material is functionalized with substance selected from
the group consisting of peptides, proteins such as antibodies,
chemical agents, active pharmaceutical ingredients (API), organic
or inorganic polymers or molecules and combinations thereof.
[0217] 7. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said the carrier with its functionalization is used for
specifically binding to receptors, proteins and macromolecules at
the cellular level in order to prevent and minimize pathogen entry
to the host target tissues by competitive inhibition.
[0218] 8. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, said
method comprising loading drugs, API, molecules, peptides inside or
onto the carrier system.
[0219] 9. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments,
comprising a functionalized and drug loaded carrier, said carrier
being used for targeted drug delivery of anti-pathogenic,
anti-viral or anti-microbial compounds in order to decrease the
growth of the pathogen, such as infectious agent.
[0220] 10. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle and/or microparticle is used for
reducing the spread of SARS-CoV-2 virus or other viruses that
causes a respiratory infection, diarrhea, common cold, influenzas
or generally discomfort or a combination thereof.
[0221] 11. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle has a 3D-configuration generally
matching the characteristics of the SARS-CoV-2 virus or influenza
viruses, rhinoviruses, common cold viruses and/or noroviruses, in
particular the particle is fabricated to a size of around 100 nm
and coated with similar amino acids as the glycoprotein spikes or
other protruding proteins at the surface of the viral particle or
similar molecules that mimic the surface of the viral envelope and
thus binds to the same target receptor as the virus.
[0222] 12. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle resembles the SARS-CoV-2 virus or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses or is optimized for competitive inhibition.
[0223] 13. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 12, wherein the synthetic carrier
exhibits a modified particle morphology, size or surface properties
to achieve increased affinity for the target receptor angiotensin
converting enzyme 2 (ACE-2) compared with the SARS-CoV-2 virus or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses, in particular for increasing the binding affinity for
the specific receptor e.g., silicid sialic acid, histo-blood group
antigens, ICAM-1, IGF1R blocking the internalization of the viral
envelope more efficiently and potentially prolonging the gained
viral protection.
[0224] 14. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle resembling the SARS-CoV-2 virus, or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is adapted for personalized medicine.
[0225] 15. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said the synthetic nanoparticle resembling the SARS-CoV-2 virus or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is loaded into or onto the nanoparticle for further
enhancing the anti-viral properties.
[0226] 16. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle resembling the SARS-CoV-2 virus, or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses is loaded with vehicles or proteome inhibitors for
efficiently delivering the compounds in the target tissues with
minimal off-target effects.
[0227] 17. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle is decorated with molecules that have
high affinity towards the SARS-CoV-2 virus or any other pathogen of
interest for example influenza viruses, rhinoviruses, common cold
viruses and/or noroviruses in order to bind and immobilize the
infectious agent preventing or minimizing the potential risk of
host entry.
[0228] 18. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said synthetic nanoparticle resembling the SARS-CoV-2 virus or any
other pathogen for example or influenza viruses, rhinoviruses,
common cold viruses and/or noroviruses is coated or decorated with
epitopes to be used as a vaccination at target cell populations
making the administration potentially easier for the end user e.g.
inhalation compared to intra muscular injection used in traditional
vaccinations.
[0229] 19. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said carrier is loaded, stored or dispersed in a device or vessel
capable of on-demand release of the carrier to the end-user.
[0230] 20. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said carrier system is loaded inside a dispenser such as an
inhalation device, tablet, injectable substance, cream or
ointment.
[0231] 21. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said the man-made materials is used for immobilizing specific
pathogens by adding the synthetic material in sanitation products
and disinfectants.
[0232] 22. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to any one of the preceding embodiments, wherein
said method comprises minimizing the spread of diverse pathogens by
binding to the target molecule in the hos body or binding to the
infectious agent itself and potently inhibit the spread of the
disease.
[0233] 23. Method of producing a synthetic carrier according to any
of embodiments 1 to 22, comprising the steps of
[0234] a) providing a core material, e.g. a nano- and/or
micro-material including nanoparticles, microparticles or any other
object as disclosed herein;
[0235] b) coating or functionalizing the core material with
molecules, polymers, amino acids, proteins, API, drugs or other
material as disclosed herein;
[0236] c) loading the object with compounds, molecules, drugs, API,
DNA or RNA etc.;
[0237] d) coating a second protective and/or functional layer on
top of the object in particular for increasing its resistance that
could be important in extreme environments such as the acidic
environment in the stomach; and
[0238] providing a small device, medical device, inhalation device
or aerosol, sanitation product or consumer product that on-demand
will release the containing synthetic material, particle or object
for administration.
[0239] The following embodiments are non-limiting representative
configurations of the present technology. The following is a
non-exclusive list of embodiments, and as such, should not be seen
to limit, in any way, the various inventions disclosed herein.
[0240] 1. A method of preventing or reducing pathogen binding, in
particular of preventing or reducing binding of SARS-CoV-2 or
influenza viruses, rhinoviruses, common cold viruses and/or
noroviruses and viral strains thereof, to target areas of cell
surfaces of a host selected from mammals, comprising providing
administering to the mammal a carrier comprising biocompatible
particles having a maximum size in at least one dimension in the
nanometer or micrometer range, forming a core, and further having a
functionalized surface capable of binding to said target areas of
said cell surfaces to at least temporarily block said target areas
to prevent or minimize pathogen binding and thus, reducing the risk
of the host contracting a disease caused by said pathogen.
[0241] 2. The method according to embodiment 1, wherein the carrier
has the capacity of binding and encapsulating the pathogen, thus
immobilizing the pathogens ability to bind and entry to the host
lowering the risk of contracting the specific infectious agent.
[0242] 3. The method according to embodiment 1 or 2, wherein the
carrier has the capacity of binding and encapsulating the pathogen
thus immobilizing the pathogens ability to bind and enter the host
and capable of binding to said target areas of said cell surfaces
to at least temporarily block viral entry, thus having dual
targeting strategies thus significantly hinder the pathogens
ability to bind and entry to the host lowering the risk of
contracting the specific infectious agent.
[0243] 4. The method according to embodiment 1 to 3, wherein the
core structure of the carrier is being obtained by 3D printing,
microfluidics, sol-gel method or other bottom-up and/or top-down
method of fabrication.
[0244] 5. The method according to any of embodiments 1 to 4,
wherein the core material comprises organic or inorganic
components, lipid droplets, amino acids, proteins, salts and
minerals or other molecules or wherein the core material comprises
mesoporous silica nanoparticles, in particular mesoporous silica
particles with ordered mesostructures of pores that preferably are
capable of being loaded with drugs.
[0245] 6. The method according to any of embodiments 1 to 5,
wherein the core material is functionalized with substance selected
from the group consisting of peptides, proteins such as antibodies,
chemical agents, active pharmaceutical ingredients (API), organic
or inorganic polymers or molecules and combinations thereof.
[0246] 7. The method according to any of embodiments 1 to 6,
wherein the carrier functionalized for specifically binding to
receptors, proteins and macromolecules at the cellular level in
order to prevent and minimize pathogen entry to the host target
tissues by competitive inhibition.
[0247] 8. The method according to any of embodiments 1 to 7,
wherein the synthetic nanoparticle and/or microparticle is used for
reducing the spread of SARS-CoV-2 virus or other viruses that
causes a respiratory infection, diarrhea, common cold, influenzas
or generally discomfort or a combination thereof.
[0248] 9. The method according to any of embodiments 1 to 8,
wherein said synthetic nanoparticle has a 3D-configuration
generally matching the characteristics of the SARS-CoV-2 virus or
other viruses that causes a respiratory infection, diarrhea, common
cold, influenzas or generally discomfort or a combination thereof,
in particular the particle is fabricated to a size of around 100 nm
and coated with similar amino acids as the glycoprotein spikes at
the surface of the viral particle or similar molecules that mimic
the surface of the viral envelope.
[0249] 10. The method according to any of embodiments 1 to 9,
wherein said synthetic nanoparticle resembles the SARS-CoV-2 virus
or other viruses that causes a respiratory infection, diarrhea,
common cold, influenzas or generally discomfort or a combination
thereof, or is optimized for competitive inhibition.
[0250] 11. The method according to any of embodiments 1 to 10,
wherein the synthetic carrier exhibits a modified particle
morphology, size or surface properties to achieve increased
affinity for the target receptor angiotensin converting enzyme 2
(ACE2) compared with the SARS-CoV-2 virus or other viruses that
causes a respiratory infection, diarrhea, common cold, influenzas
or generally discomfort or a combination thereof, in particular for
increasing the binding affinity for the specific receptor e.g.,
silicid sialic acid, histo-blood group antigens, ICAM-1, IGF1R
blocking the internalization of the viral envelope more efficiently
and potentially prolonging the gained viral protection.
[0251] 12. The method according to any of embodiments 1 to 11,
wherein said synthetic nanoparticle resembling the SARS-CoV-2 virus
or other viruses that causes a respiratory infection, diarrhea,
common cold, influenzas or generally discomfort or a combination
thereof. is adapted for personalized medicine.
[0252] 13. The method according to any of embodiments 1 to 12,
wherein said the synthetic nanoparticle resembling the SARS-CoV-2
virus or other viruses that causes a respiratory infection,
diarrhea, common cold, influenzas or generally discomfort or a
combination thereof. is loaded into or onto the nanoparticle for
further enhancing the anti-viral properties.
[0253] 14. The method according to any of embodiments 1 to 13,
wherein said synthetic nanoparticle resembling the SARS-CoV-2 virus
or other viruses that causes a respiratory infection, diarrhea,
common cold, influenzas or generally discomfort or a combination
thereof. is loaded with vehicles or proteome inhibitors for
efficiently delivering the compounds in the target tissues with
minimal off-target effects.
[0254] 15. The method according to any of embodiments 1 to 14,
wherein the synthetic nanoparticle is decorated with molecules that
have high affinity towards the SARS-CoV-2 virus or any other
pathogen of interest for example influenzas, rhinoviruses and
viruses causing respiratory infection in order to bind and
immobilize the infectious agent preventing or minimizing the
potential risk of host entry.
[0255] 16. The method according to any of embodiments 1 to 15,
wherein the synthetic nanoparticle resembling the SARS-CoV-2 virus
or any other pathogen for example influenzas, rhinoviruses and
viruses causing respiratory infection is coated or decorated with
epitopes to be used as a vaccination at target cell
populations.
[0256] 17. The method according to any of embodiments 1 to 16,
wherein the carrier is loaded, stored or dispersed in a device or
vessel capable of on-demand release of the carrier to the
end-user.
[0257] 18. The method according to any of embodiments 1 to 17,
wherein the carrier system is loaded inside a dispenser such as an
inhalation device, tablet, injectable substance, cream or
ointment.
[0258] 19. The method according to any of embodiments 1 to 18,
wherein the man-made materials is used for immobilizing specific
pathogens by adding the synthetic material in sanitation products
and disinfectants.
[0259] 20. The method according to any of embodiments 1 to 19 for
preventing or reducing pathogen binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said method comprises minimizing the spread of
diverse pathogens by binding to the target molecule in the hos body
or binding to the infectious agent itself and potently inhibit the
spread of the disease.
[0260] The following embodiments are disclosed. The following is a
non-exclusive list of embodiments, and as such, should not be seen
to limit, in any way, the various inventions disclosed herein.
[0261] 1. A synthetic carrier for use in a method of preventing or
reducing binding of a pathogen to target areas of cell structures
of a host, said carrier comprising biocompatible particles having a
maximum size in at least one dimension in the nanometer or
micrometer range, forming a core, and further having a
functionalized surface, which preferably mimics that of the
pathogen capable of binding to said target areas of said cell
surfaces to at least temporarily block said target areas to prevent
or minimize pathogen binding and thus, reducing the risk of the
host contracting a disease caused by said pathogen.
[0262] 2. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 1, wherein the pathogen is a
coronavirus, in particular SARS-CoV-2 or viral strains derived
thereof.
[0263] 3. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 1, wherein the cell structures are
selected from ACE2 and TMPRSS2 receptors and combinations
thereof.
[0264] 4. The synthetic carrier for use in a method of preventing
or reducing pathogen binding to target areas of cell structures of
a host according to embodiment 1 or 2, said carrier having the
capacity of binding and encapsulating the pathogens co-receptors
e.g., high-density lipoprotein (HDL) scavenger receptor B type 1
(SR-B1), thus immobilizing the pathogens ability to bind and entry
to the host lowering the risk of contracting the specific
infectious agent.
[0265] 5. The synthetic carrier for use in a method of preventing
or reducing pathogen coronaviruses, such as SARS-CoV-2, binding to
target areas of cell structures of a host according to any of
embodiments 1 to 3, wherein said core structure of the carrier is
being obtained by 3D printing, microfluidics, sol-gel method or
other bottom-up and/or top-down method of fabrication, and wherein
the core material comprises organic or inorganic components, lipid
droplets, amino acids, proteins, salts and minerals or other
molecules.
[0266] 6. The synthetic carrier for use in a method of preventing
or reducing pathogen, in particular coronaviruses binding to target
areas of cell structures of a host according to any one of the
preceding embodiments, wherein the core material comprises
inorganic silica nanoparticles, in particular mesoporous silica
particles, such particles preferably having ordered mesostructures
of pores that preferably are capable of being loaded with
drugs.
[0267] 7. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said core material is functionalized with
substance selected from the group consisting of peptides, proteins
such as antibodies, chemical agents, active pharmaceutical
ingredients (API), organic or inorganic polymers or molecules and
combinations thereof, and wherein said carrier with its
functionalization is preferably used for specifically binding to
receptors, proteins and macromolecules at the cellular level in
order to prevent and minimize novel coronaviruses such as
SARS-CoV-2 entry to the host target cells by competitive
inhibition.
[0268] 8. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, said method comprising loading drugs, API, molecules,
peptides inside or onto the carrier system, wherein the carrier
preferably comprises a functionalized and drug loaded carrier, said
carrier being used for targeted drug delivery of anti-viral in
order to decrease the replication of the virus inside the host
cell.
[0269] 9. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle and/or
microparticle is used for reducing the spread of SARS-CoV-2 or
other coronaviruses strains and/or types derived from the
SARS-CoV-2 that causes a respiratory infection, diarrhea, common
cold, cytokine storm, death or generally discomfort or a
combination thereof.
[0270] 10. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle has a
3D-configuration generally matching the characteristics of the
SARS-CoV-2 virus or future variants thereof, in particular the
particle is fabricated to a size of around 100-120 nm and coated
with similar amino acids as the glycoprotein spikes at the surface
of the viral particle or similar molecules that mimic the surface
of the viral envelope e.g. spike protein and thus binds to the same
target receptor as the virus.
[0271] 11. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle resembles the
SARS-CoV-2 virus or is optimized for competitive inhibition,
wherein preferably the synthetic carrier exhibits a modified
particle morphology, size or surface properties to achieve
increased affinity for the target receptor ACE2 and/or TMPRSS2,
compared with the SARS-CoV-2 virus, in particular for increasing
the binding affinity for the specific receptor blocking the
internalization of the viral envelope more efficiently and
potentially prolonging the gained viral protection.
[0272] 12. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle resembling the
SARS-CoV-2 virus is adapted for personalized medicine.
[0273] 13. The synthetic carrier for use in a method of preventing
or reducing coronavirus binding to target areas of cell structures
of a host according to any one of the preceding embodiments,
wherein said synthetic nanoparticle resembling the SARS-CoV-2 virus
is adapted for personalized medicine in the case of ACE2 receptor
polymorphism or different animal host organisms for achieving
receptor interaction.
[0274] 14. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle resembling the
SARS-CoV-2 virus is loaded into or onto the nanoparticle for
further enhancing the anti-viral properties, or wherein said
synthetic nanoparticle resembling the SARS-CoV-2 virus is loaded
with vehicles or proteome inhibitors for efficiently delivering the
compounds in the target cell and tissues with minimal off-target
effects.
[0275] 15. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said carrier is loaded, stored or dispersed in
a device or vessel capable of on-demand release of the carrier to
the end-user, wherein said carrier system is preferably loaded
inside a dispenser such as an inhalation device, tablet, injectable
substance, cream or ointment.
[0276] 16. The synthetic carrier for use in a method of preventing
or reducing coronaviruses binding to target areas of cell
structures of a host according to any one of the preceding
embodiments, wherein said synthetic nanoparticle is a
self-assembling recombinant protein-based nanoparticle construct,
such as a SpyTag/SpyCatcher system
[0277] 17. Method of producing a synthetic carrier according to any
of embodiments 1 to 16, comprising the steps of
[0278] a) providing a core material, e.g. a nano- and/or
micro-material including nanoparticles, microparticles or any other
object as disclosed herein;
[0279] b) coating or functionalizing the core material with
molecules, polymers, amino acids, proteins, API, drugs or other
material as disclosed herein;
[0280] c) loading the object with compounds, molecules, drugs, API,
DNA or RNA etc.;
[0281] d) coating a second protective and/or functional layer on
top of the object in particular for increasing its resistance that
could be important in extreme environments such as the acidic
environment in the stomach; and
[0282] providing a small device, medical device, inhalation device
or aerosol, sanitation product or consumer product that on-demand
will release the containing synthetic material, particle or object
for administration.
[0283] It will be obvious to a person skilled in the art that, as
the technology advances, the inventive concept can be implemented
in various ways. The invention and its embodiments are not limited
to the examples described above but may vary within the scope of
the claims.
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[0311] Although several embodiments and examples are disclosed
herein, the present application extends beyond the specifically
disclosed embodiments to other alternative embodiments and/or uses
of the inventions and modifications and equivalents thereof. It is
also contemplated that various combinations or subcombinations of
the specific features and aspects of the embodiments may be made
and still fall within the scope of the inventions. Accordingly, it
should be understood that various features and aspects of the
disclosed embodiments can be combined with or substituted for one
another in order to form varying modes of the disclosed inventions.
Thus, it is intended that the scope of the present inventions
herein disclosed should not be limited by the particular disclosed
embodiments described above, but should be determined only by a
fair reading of the claims that follow.
[0312] While the inventions are susceptible to various
modifications, and alternative forms, specific examples thereof
have been shown in the drawings and are herein described in detail.
It should be understood, however, that the inventions are not to be
limited to the particular forms or methods disclosed, but, to the
contrary, the inventions are to cover all modifications,
equivalents, and alternatives falling within the spirit and scope
of the various embodiments described and the appended claims. Any
methods disclosed herein need not be performed in the order
recited. The methods summarized above and set forth in further
detail below describe certain actions taken by a practitioner;
however, it should be understood that they can also include the
instruction of those actions by another party. The methods
summarized above and set forth in further detail below describe
certain actions taken by a user (e.g., a professional in some
instances); however, it should be understood that they can also
include the instruction of those actions by another party. Thus,
actions such as "delivering" include "instructing delivering." The
ranges disclosed herein also encompass any and all overlap,
sub-ranges, and combinations thereof. Language such as "up to," "at
least," "greater than," "less than," "between," and the like
includes the number recited. Numbers proceeded by a term such as
"about" or "approximately" include the recited numbers. For
example, "about 10 mm" includes "10 mm." Terms or phrases preceded
by a term such as "substantially" include the recited term or
phrase. For example, "substantially parallel" includes "parallel."
Sequence CWU 1
1
716PRTSARS-CoV-2 1Tyr Lys Tyr Arg Tyr Leu1 526PRTArtificial
SequencePotential alternative synthetic hexapeptide variant 2Tyr
Lys Tyr Asn Tyr Ile1 536PRTArtificial SequencePotential alternative
synthetic hexapeptide variant 3Tyr Lys Tyr Asn Tyr Leu1
5428PRTSARS-CoV-2 4Lys Lys Lys Lys Val Cys Glu Phe Gln Phe Cys Asn
Asp Pro Phe Leu1 5 10 15Gly Val Tyr Tyr His Lys Asn Asn Lys Lys Lys
Lys 20 255223PRTSARS-CoV-2 5Arg Val Gln Pro Thr Glu Ser Ile Val Arg
Phe Pro Asn Ile Thr Asn1 5 10 15Leu Cys Pro Phe Gly Glu Val Phe Asn
Ala Thr Arg Phe Ala Ser Val 20 25 30Tyr Ala Trp Asn Arg Lys Arg Ile
Ser Asn Cys Val Ala Asp Tyr Ser 35 40 45Val Leu Tyr Asn Ser Ala Ser
Phe Ser Thr Phe Lys Cys Tyr Gly Val 50 55 60Ser Pro Thr Lys Leu Asn
Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp65 70 75 80Ser Phe Val Ile
Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln 85 90 95Thr Gly Lys
Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr 100 105 110Gly
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly 115 120
125Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys
130 135 140Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly
Ser Thr145 150 155 160Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr
Phe Pro Leu Gln Ser 165 170 175Tyr Gly Phe Gln Pro Thr Asn Gly Val
Gly Tyr Gln Pro Tyr Arg Val 180 185 190Val Val Leu Ser Phe Glu Leu
Leu His Ala Pro Ala Thr Val Cys Gly 195 200 205Pro Lys Lys Ser Thr
Asn Leu Val Lys Asn Lys Cys Val Asn Phe 210 215
22061273PRTSARS-CoV-2 6Met Phe Val Phe Leu Val Leu Leu Pro Leu Val
Ser Ser Gln Cys Val1 5 10 15Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro
Ala Tyr Thr Asn Ser Phe 20 25 30Thr Arg Gly Val Tyr Tyr Pro Asp Lys
Val Phe Arg Ser Ser Val Leu 35 40 45His Ser Thr Gln Asp Leu Phe Leu
Pro Phe Phe Ser Asn Val Thr Trp 50 55 60Phe His Ala Ile His Val Ser
Gly Thr Asn Gly Thr Lys Arg Phe Asp65 70 75 80Asn Pro Val Leu Pro
Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr Glu 85 90 95Lys Ser Asn Ile
Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp Ser 100 105 110Lys Thr
Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val Ile 115 120
125Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val Tyr
130 135 140Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg
Val Tyr145 150 155 160Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val
Ser Gln Pro Phe Leu 165 170 175Met Asp Leu Glu Gly Lys Gln Gly Asn
Phe Lys Asn Leu Arg Glu Phe 180 185 190Val Phe Lys Asn Ile Asp Gly
Tyr Phe Lys Ile Tyr Ser Lys His Thr 195 200 205Pro Ile Asn Leu Val
Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu Glu 210 215 220Pro Leu Val
Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln Thr225 230 235
240Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser Ser
245 250 255Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu
Gln Pro 260 265 270Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr
Ile Thr Asp Ala 275 280 285Val Asp Cys Ala Leu Asp Pro Leu Ser Glu
Thr Lys Cys Thr Leu Lys 290 295 300Ser Phe Thr Val Glu Lys Gly Ile
Tyr Gln Thr Ser Asn Phe Arg Val305 310 315 320Gln Pro Thr Glu Ser
Ile Val Arg Phe Pro Asn Ile Thr Asn Leu Cys 325 330 335Pro Phe Gly
Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr Ala 340 345 350Trp
Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val Leu 355 360
365Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser Pro
370 375 380Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp
Ser Phe385 390 395 400Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala
Pro Gly Gln Thr Gly 405 410 415Lys Ile Ala Asp Tyr Asn Tyr Lys Leu
Pro Asp Asp Phe Thr Gly Cys 420 425 430Val Ile Ala Trp Asn Ser Asn
Asn Leu Asp Ser Lys Val Gly Gly Asn 435 440 445Tyr Asn Tyr Leu Tyr
Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro Phe 450 455 460Glu Arg Asp
Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro Cys465 470 475
480Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr Gly
485 490 495Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val
Val Val 500 505 510Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val
Cys Gly Pro Lys 515 520 525Lys Ser Thr Asn Leu Val Lys Asn Lys Cys
Val Asn Phe Asn Phe Asn 530 535 540Gly Leu Thr Gly Thr Gly Val Leu
Thr Glu Ser Asn Lys Lys Phe Leu545 550 555 560Pro Phe Gln Gln Phe
Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala Val 565 570 575Arg Asp Pro
Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser Phe 580 585 590Gly
Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln Val 595 600
605Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala Ile
610 615 620His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr
Gly Ser625 630 635 640Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile
Gly Ala Glu His Val 645 650 655Asn Asn Ser Tyr Glu Cys Asp Ile Pro
Ile Gly Ala Gly Ile Cys Ala 660 665 670Ser Tyr Gln Thr Gln Thr Asn
Ser Pro Arg Arg Ala Arg Ser Val Ala 675 680 685Ser Gln Ser Ile Ile
Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn Ser 690 695 700Val Ala Tyr
Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr Ile705 710 715
720Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser Val
725 730 735Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser
Asn Leu 740 745 750Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn
Arg Ala Leu Thr 755 760 765Gly Ile Ala Val Glu Gln Asp Lys Asn Thr
Gln Glu Val Phe Ala Gln 770 775 780Val Lys Gln Ile Tyr Lys Thr Pro
Pro Ile Lys Asp Phe Gly Gly Phe785 790 795 800Asn Phe Ser Gln Ile
Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg Ser 805 810 815Phe Ile Glu
Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala Gly 820 825 830Phe
Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg Asp 835 840
845Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro Leu
850 855 860Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu
Ala Gly865 870 875 880Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly
Ala Ala Leu Gln Ile 885 890 895Pro Phe Ala Met Gln Met Ala Tyr Arg
Phe Asn Gly Ile Gly Val Thr 900 905 910Gln Asn Val Leu Tyr Glu Asn
Gln Lys Leu Ile Ala Asn Gln Phe Asn 915 920 925Ser Ala Ile Gly Lys
Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser Ala 930 935 940Leu Gly Lys
Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu Asn945 950 955
960Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser Val
965 970 975Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu
Val Gln 980 985 990Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu
Gln Thr Tyr Val 995 1000 1005Thr Gln Gln Leu Ile Arg Ala Ala Glu
Ile Arg Ala Ser Ala Asn 1010 1015 1020Leu Ala Ala Thr Lys Met Ser
Glu Cys Val Leu Gly Gln Ser Lys 1025 1030 1035Arg Val Asp Phe Cys
Gly Lys Gly Tyr His Leu Met Ser Phe Pro 1040 1045 1050Gln Ser Ala
Pro His Gly Val Val Phe Leu His Val Thr Tyr Val 1055 1060 1065Pro
Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile Cys His 1070 1075
1080Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val Ser Asn
1085 1090 1095Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu
Pro Gln 1100 1105 1110Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly
Asn Cys Asp Val 1115 1120 1125Val Ile Gly Ile Val Asn Asn Thr Val
Tyr Asp Pro Leu Gln Pro 1130 1135 1140Glu Leu Asp Ser Phe Lys Glu
Glu Leu Asp Lys Tyr Phe Lys Asn 1145 1150 1155His Thr Ser Pro Asp
Val Asp Leu Gly Asp Ile Ser Gly Ile Asn 1160 1165 1170Ala Ser Val
Val Asn Ile Gln Lys Glu Ile Asp Arg Leu Asn Glu 1175 1180 1185Val
Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln Glu Leu 1190 1195
1200Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile Trp Leu
1205 1210 1215Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr
Ile Met 1220 1225 1230Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu
Lys Gly Cys Cys 1235 1240 1245Ser Cys Gly Ser Cys Cys Lys Phe Asp
Glu Asp Asp Ser Glu Pro 1250 1255 1260Val Leu Lys Gly Val Lys Leu
His Tyr Thr 1265 12707272PRTArtificial
SequenceSyntheticMISC_FEATURE(1)..(49)Different Expression Cassette
- Signal Sequence - Tag - Spacer; X is any amino acid 7Xaa Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa1 5 10 15Xaa Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 20 25 30Xaa
Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa 35 40
45Xaa Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr
50 55 60Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala
Ser65 70 75 80Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val
Ala Asp Tyr 85 90 95Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe
Lys Cys Tyr Gly 100 105 110Val Ser Pro Thr Lys Leu Asn Asp Leu Cys
Phe Thr Asn Val Tyr Ala 115 120 125Asp Ser Phe Val Ile Arg Gly Asp
Glu Val Arg Gln Ile Ala Pro Gly 130 135 140Gln Thr Gly Lys Ile Ala
Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe145 150 155 160Thr Gly Cys
Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val 165 170 175Gly
Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu 180 185
190Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser
195 200 205Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro
Leu Gln 210 215 220Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr
Gln Pro Tyr Arg225 230 235 240Val Val Val Leu Ser Phe Glu Leu Leu
His Ala Pro Ala Thr Val Cys 245 250 255Gly Pro Lys Lys Ser Thr Asn
Leu Val Lys Asn Lys Cys Val Asn Phe 260 265 270
* * * * *
References