Twin Base Linkers for Virus Inactivation

Abstract

Functionalized twin base linkers (TBLs) bind to and deactivate viruses by preventing their entry into cells. Functionalization of TBLs allows them to specifically bind to surface proteins of viruses, where they form structures that limit virus entry into cells and prevent viruses from replicating.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63/010,642, filed 15 Apr. 2020, which is incorporated by reference herein in its entirety.

BACKGROUND

[0002] Twin base linkers (TBLs) are biocompatible, biodegradable polymers capable of self-assembly to form rosette nanotubes (RNTs) under physiological conditions. TBLs have been suggested for use in drug delivery due to the presence of a hollow core in RNTs that can accommodate drugs, including hydrophobic drugs (Song, et al. (2011)). TBLs contain covalently linked pairs of guanine-like and cytosine-like bases. Six such pairs form a six-member twin rosette stabilized by 36 hydrogen bonds, and the rosettes stack to form RNTs due to dispersion forces, base stacking interactions, and hydrophobic bonding (Fenniri, et al., 2001). The outer surface of RNTs is hydrophilic, rendering them water soluble. RNTs have been shown to bind to cells, to enhance cell growth, and to have other beneficial actions on cells and tissues.

SUMMARY

[0003] The present technology provides targeted twin base linkers (TBLs) to bind to and deactivate viruses by preventing their entry into cells. TBLs are formed from two linked nucleic acid bases and have guanine- and cytosine-like hydrogen bond pairing capability. Monomeric units of TBLs are capable of self-assembly to form supramolecular structures such as hollow nanotubules and other structures.

[0004] Functionalization of TBLs in the present technology allows them to specifically bind to surface proteins of viruses, where they form structures that can attach to viruses, limit virus entry into cells, and prevent viruses from replicating.

[0005] The technology is further summarized by the following listing of features.

1. An antiviral composition comprising a plurality of functionalized twin base linker (TBL) molecules having the general structure

##STR00001##

[0006] wherein the twin bases comprise a structure according to Formula 1

##STR00002##

[0007] wherein L is the linker and comprises carbon, nitrogen, and/or oxygen atoms and has a chain length from about 4 to about 20 atoms;

[0008] wherein the peptide moiety contains from about 2 to about 20 L- and/or D-amino acids; and

[0009] wherein optionally one or more targeting moieties are covalently linked to the peptide, the targeting moieties capable of specifically binding a surface-accessible protein of a virus, thereby deactivating the virus, or wherein the targeting moieties are absent, and the peptide moiety is capable of specifically binding a surface-accessible protein of a virus, thereby deactivating the virus.

2. The antiviral composition of feature 1, wherein the targeting moieties are present and are selected from the group consisting of antibodies, aptamers, and peptides. 3. The antiviral composition of feature 1 or feature 2, wherein the peptide comprises one or more amino acids that are positively charged at pH 7 and/or one or more amino acids that are negatively charged at pH 7. 4. The antiviral composition of any of the preceding features, wherein the functionalized TBL molecules comprise one or more targeting moieties covalently attached to the peptide moiety, and wherein the one or more targeting moieties are peptides, each peptide having an amino acid sequence that is distinct from that of the peptide moiety. 5. The antiviral composition of any of the preceding features, wherein the functionalized TBL molecules comprise a peptide moiety or a targeting moiety that binds to a virus spike protein, a virus envelope protein, or both. 6. The antiviral composition of feature 5, wherein the peptide moiety or a targeting moiety comprise a peptide selected from the group consisting of SADE (SEQ ID NO:2), SASD (SEQ ID NO:7), SASE (SEQ ID NO:8), and SACD (SEQ ID NO:9). 7. The antiviral composition of any of the preceding features, comprising functionalized TBL molecules in monomeric form. 8. The antiviral composition of any of the preceding features, comprising functionalized TBL molecules in form of a supramolecular assembly. 9. The antiviral composition of any of the preceding features, wherein the peptide moiety or the targeting moieties bind to a protein of SARS-CoV-2 virus. 10. The antiviral composition of feature 9, wherein the peptide moiety or the targeting moieties bind to S protein of SARS-CoV-2 virus. 11. The antiviral composition of feature 10, wherein the peptide moiety or the targeting moieties also bind to E protein of SARS-CoV-2 virus. 12. The antiviral composition of any of the preceding features, wherein the functionalized TBL molecules, or a supramolecular assembly comprising the functionalized TBL molecules, is capable of inhibiting entry of the virus into a mammalian cell. 13. The antiviral composition of any of the preceding features, wherein the functionalized TBL molecules, or a supramolecular assembly comprising the functionalized TBL molecules, is capable of inhibiting death of mammalian cells infected by the virus. 14. The antiviral composition of any of the preceding features, wherein the composition is for use in treating or preventing a viral infection. 15. The antiviral composition of feature 14, wherein the viral infection is caused by a virus selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, an adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus. 16. The antiviral composition of feature 14, wherein the composition is for use in treating or preventing two or more viral infections selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, an adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus. 17. The antiviral composition of feature 16, wherein the composition is for treating or preventing infection by SARS CoV-2, influenza A virus, influenza B virus, and rhinovirus. 18. A method to aid in treating or preventing a viral infection, the method comprising administering the antiviral composition of any of the preceding features to a subject in need thereof. 19. The method of feature 18, wherein the viral infection is caused by a virus selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus. 20. The method of feature 19, wherein the virus is SARS-CoV-2. 21. The method of any of features 18-20, wherein cellular entry of a virus, virus replication, and/or one or more symptoms of the viral infection are reduced or prevented in the subject.

[0010] As used herein, the term "about" refers to a range of within plus or minus 10%, 5%, 1%, or 0.5% of the stated value.

[0011] As used herein, "consisting essentially of" allows the inclusion of materials or steps that do not materially affect the basic and novel characteristics of the claim. Any recitation herein of the term "comprising", particularly in a description of components of a composition or in a description of elements of a device, can be exchanged with the alternative expression "consisting of" or "consisting essentially of".

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1A shows a twin base G{circumflex over ( )}C motif functionalized with an aminobutyl linker.

[0013] FIG. 1B shows a twin base G{circumflex over ( )}C module functionalized with a propionyl linker, which is connected via a peptide bond to a KRSR (SEQ ID NO:1) tetrapeptide. FIG. 1C shows a schematic diagram of a targeted twin base linker motif, in which the peptide moiety is covalently linked through amino acid side chains to targeting moieties.

[0014] FIG. 2A shows a prior art model of a rosette structure formed by association of six twin base modules through hydrogen bonds. FIG. 2B shows a prior art model of a nanotubule formed by the stacking of six rosettes such as depicted in FIG. 2A.

[0015] FIG. 3 shows a schematic representation of a process of preparing a pseudovirus containing a desired virus spike protein and expressing green fluorescent protein (GFP) or luciferase after infection of target cells.

[0016] FIGS. 4A-4C show results of infecting HEK293T cells with a pseudovirus displaying the spike protein of SARS-CoV-2, and expressing GFP in the infected cells. The vertical axis represents arbitrary units of fluorescence, and the horizonal groupings represent pseudovirus concentration (copies/.mu.L) added to the medium. Each grouping of bars shows the concentration of TBL present (left to right: 0, 1 mg/mL, 0.1 mg/mL, 0.01 mg/mL, and 0.001 mg/mL). All amounts of TBL were significantly different (p<0.01) from no TBL. Number of cells was constant for all assays. TBL was functionalized with SADE (SEQ ID NO:2) (SEQ ID NO:2) peptide. Time of incubation of the cells with pseudovirus was 15 min (FIG. 4A), 1 hour (FIG. 4B), or 4 hours (FIG. 4C). All controls (no cells, no pseudovirus) showed no fluorescence.

[0017] FIGS. 5A-5C show results of infecting HEK293T cells with a pseudovirus displaying the spike protein of the B117 variant of SARS-CoV-2, and expressing GFP in the infected cells. The vertical axis represents arbitrary units of fluorescence, and the horizonal groupings represent pseudovirus concentration (copies/.mu.L) added to the medium. Each grouping of bars shows the concentration of TBL present (left to right: 0, 1 mg/mL, 0.1 mg/mL, 0.01 mg/mL, and 0.001 mg/mL). All amounts of TBL were significantly different (p<0.01) from no TBL. Number of cells was constant for all assays. TBL was functionalized with SADE (SEQ ID NO:2) peptide. Time of incubation of the cells with pseudovirus was 15 min (FIG. 5A), 1 hour (FIG. 5B), or 4 hours (FIG. 5C).

[0018] FIGS. 6A-6C show results of infecting HEK293T cells with a pseudovirus displaying the spike protein of the 501 YV2 variant of SARS-CoV-2, and expressing GFP in the infected cells. The vertical axis represents arbitrary units of fluorescence, and the horizonal groupings represent pseudovirus concentration (copies/.mu.L) added to the medium. Each grouping of bars shows the concentration of TBL present (left to right: 0, 1 mg/mL, 0.1 mg/mL, 0.01 mg/mL, and 0.001 mg/mL). All amounts of TBL were significantly different (p<0.01) from no TBL. Number of cells was constant for all assays. TBL was functionalized with SADE (SEQ ID NO:2) peptide. Time of incubation of the cells with pseudovirus was 15 min (FIG. 6A), 1 hour (FIG. 6B), or 4 hours (FIG. 6C).

[0019] FIG. 7 shows results of an experiment to test the ability of functionalized TBL-SADE (SEQ ID NO:2) to protect normal human adult dermal fibroblasts (HDFa from ATCC) from death caused by infection with rhinovirus. Vertical axis shows fluorescence (arbitrary units; Live and Dead Cell Assay by Abcam) indicating dead cells, while the horizonal axis shows the rhinovirus concentration in copies/.mu.L. Concentrations of 0.01 to 1 mg/mL of TBL-SADE inhibited cell death by 96% to 98%.

[0020] FIGS. 8A-8B show protection by TBL-SADE of human adult dermal fibroblasts from death by infection with influenza A (FIG. 8A) or influenza B (FIG. 8B) virus. Inhibition was 45% to 55% for influenza A and 42% to 48% for influenza B. Vertical axis shows fluorescence (arbitrary units; Live and Dead Cell Assay by Abcam) indicating dead cells, while the horizonal axis shows the virus concentration in copies/.mu.L

DETAILED DESCRIPTION

[0021] The present technology makes use of targeted twin base linkers (TBLs) to bind to and deactivate viruses. TBLs are capable of self-assembly to form supramolecular nanotubules. Such nanomaterials can attach to viruses, limit virus entry into cells, and prevent viruses from replicating.

[0022] Viruses are nanoscale structures and, according to the present technology, viruses can be deactivated by the binding of certain other nanoscale structures, including the macromolecular complexes known as twin base linkers. In the present technology, virus entry into target cells is blocked using a nanomaterial that binds to a structure of the virus involved in cellular entry. The entry and infection of a cell by a virus is a multi-step process, the first step of which is the attachment of the virus to receptor molecules at the surface of the target cell. Although nanomaterials can deactivate many viruses, such as those infecting mammalian cells, including human cells, SARS-CoV-2 is discussed below as an example. The technology can be applied to any virus that infects mammalian cells.

[0023] Coronaviruses, including the SARS-CoV-2 virus which causes COVID 19, contain round shells of protein molecules that protect the RNA genetic material. Surrounding the shell is a lipid bilayer membrane containing "spike" proteins (S) that contain the site for binding the cellular receptor on the target cell (see, e.g., R. Al-Attabi, et al., 2019). TBL-derived nanomaterials can be targeted to the S protein so that the nanomaterials bind to the region of the virus that is active in promoting cellular entry.

[0024] According to the present technology, functionalized TBLs bind a target on the virus, such as the S protein of SARS-CoV-2. While not intending to limit the technology to any particular mechanism, it is believed that the TBLs form a supramolecular structure that wraps around the virus particle, in whole or in part, thereby preventing it from attaching to the target cell of the virus. A functionalized TBL monomer or motif of the present technology can have the general structure depicted in FIG. 1A, for example. The TBL monomer or motif can have a structure as depicted in Formula 1 below.

##STR00003##

The twin guanine-like and cytosine-like bases can be attached via a linker, L, such as a diaminobutane moiety, a butyric acid moiety, or other linker, to a peptide. The linker can be a straight or branched chain containing from 2 to 20 carbon atoms; preferably the linker is covalently bound at a first end to a nitrogen atom of the TBL monomer and at a second end is covalently bound via a peptide linkage to the peptide moiety of the TBL. The peptide can be of any desired length, and can itself be used as a targeting moiety capable of binding to the virus binding site, or optionally can serve as a backbone to which is attached one or more optional separate targeting moieties, which can be either identical or non-identical. The targeting moieties can be, for example, peptides, oligopeptides, antibodies, including target-binding fragments thereof, or single chain recombinant antibodies, or aptamers, and can be attached via covalent bonds to amino acid side chains or a terminal NH.sub.2 or COOH group of the peptide moiety, which then serves as a backbone. Alternatively, the backbone can be a nucleic acid (DNA, RNA, or synthetic), a polysaccharide such as dextran, or another polymer. Small peptides are preferred as the targeting moieties, such as peptides containing from 2 to 20 amino acids, or 2-10, 3-12, 4-10, or 4-20 amino acids, such as peptides containing 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids.

[0025] The targeting moieties are selected to provide high affinity binding to the virus. Given that the virus particle contains multiple copies of the virus binding site, the affinity of the functionalized TBL monomers or self-assembled TBL nanostructures containing such monomers can be significantly enhanced by utilizing multiple copies of the targeting moiety, through cooperativity of binding. In addition to high affinity binding provided by one or more targeting moieties attached to the TBL monomers, the twin bases of the TBLs themselves can contribute to high affinity binding through hydrogen bonding between the bases and suitable functional groups on the virus, such as amino acids of the S protein.

[0026] For SARS-CoV-2, a preferred binding for TBLs is the receptor binding domain of the S protein, which binds to the natural target of the virus, angiotensin converting enzyme 2 (ACE2). Thus, targeting moieties can be, for example, antibodies or aptamers binding to epitopes within the receptor binding domain of S protein, or peptide fragments of ACE2 that bind to the receptor binding domain of S protein, or glycosylation sites of the S protein. The known amino acid sequence and structure of the S protein, which is described in Kumar et al., 2020, or variants thereof, can be used to select suitable epitopes for targeting. For example, fragments of the receptor binding domain (amino acids 270-510) can be used as epitopes for binding with an antibody or nucleic acid aptamer. Examples of peptides that can be used to bind to and target the novel glycosylation sites (NGTK (SEQ ID NO:3), NFTI (SEQ ID NO:4), NLTT (SEQ ID NO:5), and NTSN (SEQ ID NO:6)) of the S protein of the SARS-CoV-2 virus include: SADE (SEQ ID NO:2), SASD (SEQ ID NO:7), SASE (SEQ ID NO:8), SACD (SEQ ID NO:9), SACE (SEQ ID NO:10), SAPD (SEQ ID NO:11), SAPE (SEQ ID NO:12), SAND (SEQ ID NO:13), SANE (SEQ ID NO:14), SAQD (SEQ ID NO:15), SAQE (SEQ ID NO:16), SVSD (SEQ ID NO:17), SVSE (SEQ ID NO:18), SVCD (SEQ ID NO:19), SVCE (SEQ ID NO:20), SVPD (SEQ ID NO:21), SVPE (SEQ ID NO:22), SVND (SEQ ID NO:23), SVNE (SEQ ID NO:24), SVQD (SEQ ID NO:25), SVQE (SEQ ID NO:26), SLSD (SEQ ID NO:27), SLSE (SEQ ID NO:28), SLCD (SEQ ID NO:29), SLCE (SEQ ID NO:30), SLPD (SEQ ID NO:31), SLPE (SEQ ID NO:32), SLND (SEQ ID NO:33), SLNE (SEQ ID NO:34), SLQD (SEQ ID NO:35), SLDE (SEQ ID NO:36), SMSE (SEQ ID NO:37), SMSD (SEQ ID NO:38), SMCE (SEQ ID NO:39), SMCD (SEQ ID NO:40), SMPD (SEQ ID NO:41), SMPE (SEQ ID NO:42), SMND (SEQ ID NO:43), SMNE (SEQ ID NO:44), SMQD (SEQ ID NO:45), SMQE (SEQ ID NO:46), PASD (SEQ ID NO:47), PASE (SEQ ID NO:48), PACD (SEQ ID NO:49), PACE (SEQ ID NO:50), PAPD (SEQ ID NO:51), PAPE (SEQ ID NO:52), PAND (SEQ ID NO:53), PANE (SEQ ID NO:54), PAQD (SEQ ID NO:55), PAQE (SEQ ID NO:56), PVSD (SEQ ID NO:57), PVSE (SEQ ID NO:58), PVCD (SEQ ID NO:59), PVCE (SEQ ID NO:60), PVPD (SEQ ID NO:61), PVPE (SEQ ID NO:62), PVND (SEQ ID NO:63), PVNE (SEQ ID NO:64), PVQD (SEQ ID NO:65), PVQE (SEQ ID NO:66), PLSD (SEQ ID NO:67), PLSE (SEQ ID NO:68), PLCD (SEQ ID NO:69), PLCE (SEQ ID NO:70), PLPD (SEQ ID NO:71), PLPE (SEQ ID NO:72), PLND (SEQ ID NO:73), PLNE (SEQ ID NO:74), PLQD (SEQ ID NO:75), PLQE (SEQ ID NO:76), PMSD (SEQ ID NO:77), PMSE (SEQ ID NO:78), PMCD (SEQ ID NO:79), PMCE (SEQ ID NO:80), CASD (SEQ ID NO:81), CASE (SEQ ID NO:82), CACD (SEQ ID NO:83), CACE (SEQ ID NO:84), CAPD (SEQ ID NO:85), CAPE (SEQ ID NO:86), CAND (SEQ ID NO:87), CANE (SEQ ID NO:88), CAQD (SEQ ID NO:89), CAQE (SEQ ID NO:90), CVSD (SEQ ID NO:91), CVSE (SEQ ID NO:92), CVCD (SEQ ID NO:93), CVCE (SEQ ID NO:94), CVPD (SEQ ID NO:95), CVPE (SEQ ID NO:96), CVND (SEQ ID NO:97), CVNE (SEQ ID NO:98), CVQD (SEQ ID NO:99), CVQE (SEQ ID NO:100), CLSD (SEQ ID NO:101), CLSE (SEQ ID NO:102), CLCD (SEQ ID NO:103), CLCE (SEQ ID NO:104), CLPD (SEQ ID NO:105), CLPE (SEQ ID NO:106), CLND (SEQ ID NO:107), CLNE (SEQ ID NO:108), CLQD (SEQ ID NO:109), CLQE (SEQ ID NO:110), CMSD (SEQ ID NO:111), CMSE (SEQ ID NO:112), CMCD (SEQ ID NO:113), CMSE (SEQ ID NO:114), CMPD (SEQ ID NO:115), CMPE (SEQ ID NO:116), CMND (SEQ ID NO:117), CMNE (SEQ ID NO:118), CMQD (SEQ ID NO:119), CMQE (SEQ ID NO:120), TASD (SEQ ID NO:121), TASE (SEQ ID NO:122), TACD (SEQ ID NO:123), TACE (SEQ ID NO:124), TAPD (SEQ ID NO:125), TAPE (SEQ ID NO:126), TAND (SEQ ID NO:127), TANE (SEQ ID NO:128), TAQD (SEQ ID NO:129), TAQE (SEQ ID NO:130), TVSD (SEQ ID NO:131), TVSE (SEQ ID NO:132), TVCD (SEQ ID NO:133), TVCE (SEQ ID NO:134), TVPD (SEQ ID NO:135), TVPE (SEQ ID NO:136), TVND (SEQ ID NO:137), TVNE (SEQ ID NO:138), TVQD (SEQ ID NO:139), TVQE (SEQ ID NO:140), TLSD (SEQ ID NO:141), TLSE (SEQ ID NO:142), TLCD (SEQ ID NO:143), TLCE (SEQ ID NO:144), TLPD (SEQ ID NO:145), TLPE (SEQ ID NO:146), TLND (SEQ ID NO:147), TLNE (SEQ ID NO:148), TLQD (SEQ ID NO:149), TLQE (SEQ ID NO:150), TMSD (SEQ ID NO:151), TMSE (SEQ ID NO:152), TMCD (SEQ ID NO:153), TMCE (SEQ ID NO:154), TMPD (SEQ ID NO:155), TMPE (SEQ ID NO:156), TMND (SEQ ID NO:157), TMNE (SEQ ID NO:158), TMQD (SEQ ID NO:159), TMQE (SEQ ID NO:160), QASD (SEQ ID NO:161), QASE (SEQ ID NO:162), QVCD (SEQ ID NO:163), QVCE (SEQ ID NO:164), QVPD (SEQ ID NO:165), QVPE (SEQ ID NO:166), QVND (SEQ ID NO:167), QVNE (SEQ ID NO:168), QVQD (SEQ ID NO:169), QVQE (SEQ ID NO:170), QLSD (SEQ ID NO:171), QLSE (SEQ ID NO:172), QLCD (SEQ ID NO:173), QLCE (SEQ ID NO:174), QLPD (SEQ ID NO:175), QLPE (SEQ ID NO:176), QLND (SEQ ID NO:177), QLNE (SEQ ID NO:178), QLQD (SEQ ID NO:179), QLQE (SEQ ID NO:180), QMSD (SEQ ID NO:181), QMSE (SEQ ID NO:182), QMCD (SEQ ID NO:183), QMCE (SEQ ID NO:184), QMPD (SEQ ID NO:185), QMPE (SEQ ID NO:186), QMND (SEQ ID NO:187), QMNE (SEQ ID NO:188), QMQD (SEQ ID NO:189), QMQE (SEQ ID NO:190). These tetrapeptides, or larger peptides containing them, can be used as targeting moieties.

[0027] Similar strategies can be used to select targeting moieties for other viruses. For example, binding of TBLs to the S protein of the MERS virus can be mediated using the targeting moiety peptides MIHS (SEQ ID NO:191), AIHS (SEQ ID NO:192), VIHS (SEQ ID NO:193), IIHS (SEQ ID NO:194), LIHS (SEQ ID NO:195), FIHS (SEQ ID NO:196), YIHS (SEQ ID NO:197), WIHS (SEQ ID NO:198), MAHS (SEQ ID NO:199), MVHS (SEQ ID NO:200), MLHS (SEQ ID NO:201), MMHS (SEQ ID NO:202), MFHS (SEQ ID NO:203), MYHS (SEQ ID NO:204), MWHS (SEQ ID NO:205), AIRS (SEQ ID NO:206), AIRK (SEQ ID NO:207), AIDK (SEQ ID NO:208), AIEK (SEQ ID NO:209), MIHT (SEQ ID NO:210), MIHN (SEQ ID NO:211), and/or MIHQ (SEQ ID NO:212). Binding if TBLs to the neuraminidase of the influenza Type A virus can be obtained using as targeting moiety the peptides ASCS (SEQ ID NO:213), ATCS (SEQ ID NO:214), ANCS (SEQ ID NO:215), AQCS (SEQ ID NO:216), AVCS (SEQ ID NO:217), VSCS (SEQ ID NO:218), VTCS (SEQ ID NO:219), VNCS (SEQ ID NO:220), VQCS (SEQ ID NO:221), WCS (SEQ ID NO:222), ISCS (SEQ ID NO:223), ITCS (SEQ ID NO:224), INCS (SEQ ID NO:225), IQCS (SEQ ID NO:226), IVCS (SEQ ID NO:227), LSCS (SEQ ID NO:228), LTCS (SEQ ID NO:229), LNCS (SEQ ID NO:230), LQCS (SEQ ID NO:231), MSCS (SEQ ID NO:232), MTCS (SEQ ID NO:233), MNCS (SEQ ID NO:234), MQCS (SEQ ID NO:235), MVCS (SEQ ID NO:236), FSCS (SEQ ID NO:237), FTCS (SEQ ID NO:238), FNCS (SEQ ID NO:239), FQCS (SEQ ID NO:240), FVCS (SEQ ID NO:241), YSCS (SEQ ID NO:242), YTCS (SEQ ID NO:243), YNCS (SEQ ID NO:244), YQCS (SEQ ID NO:245), YVCS (SEQ ID NO:246), WSCS (SEQ ID NO:247), WTCS (SEQ ID NO:248), WNCS (SEQ ID NO:249), WQCS (SEQ ID NO:250), and/or WVCS (SEQ ID NO:251). Binding of TBLs to VP1-VP4 in rhinovirus can be obtained using as targeting moiety the peptides MGAQ (SEQ ID NO:252): AGAQ (SEQ ID NO:253), VGAQ (SEQ ID NO:254), IGAQ (SEQ ID NO:255), LGAQ (SEQ ID NO:256), FGAQ (SEQ ID NO:257), YGAQ (SEQ ID NO:258), WGAQ (SEQ ID NO:259), ACAQ (SEQ ID NO:260), VCAQ (SEQ ID NO:261), ICAQ (SEQ ID NO:262), LCAQ (SEQ ID NO:263), MCAQ (SEQ ID NO:264), FCAQ (SEQ ID NO:265), YCAQ (SEQ ID NO:266), WCAQ (SEQ ID NO:267), APAQ (SEQ ID NO:268), VPAQ (SEQ ID NO:269), IPAQ (SEQ ID NO:270), LPAQ (SEQ ID NO:271), FPAQ (SEQ ID NO:272), YPAQ (SEQ ID NO:273), WPAQ (SEQ ID NO:274), AGVQ (SEQ ID NO:275), VGVQ (SEQ ID NO:276), IGVQ (SEQ ID NO:277), LGVQ (SEQ ID NO:278), FGVQ (SEQ ID NO:279), YGVQ (SEQ ID NO:280), WGVQ (SEQ ID NO:281), ACVQ (SEQ ID NO:282), VCVQ (SEQ ID NO:283), ICVQ (SEQ ID NO:284), LCVQ (SEQ ID NO:285), MCVQ (SEQ ID NO:286), FCVQ (SEQ ID NO:287), YCVQ (SEQ ID NO:288), WCVQ (SEQ ID NO:289), APVQ (SEQ ID NO:290), VPVQ (SEQ ID NO:291), IPVQ (SEQ ID NO:292), LPVQ (SEQ ID NO:293), FPVQ (SEQ ID NO:294), YPVQ (SEQ ID NO:295), and/or WPVQ (SEQ ID NO:296).

[0028] The TBL monomers and nanostructures of the present technology can also serve to misdirect the targeted virus. For example, either the peptide moiety of the functionalized TBL monomer or one or more of the targeting moieties attached thereto can bind to a selected cellular receptor so as to enhance binding of the virus to receptors that it cannot use to enter cells, or to direct it to cells of the immune system that can destroy it.

[0029] The present technology also includes a method to aid in treating or preventing a viral infection. The method includes administering to a subject in need thereof a composition containing a functionalized TBL monomer as described above, and/or a nanostructure formed from one or more types of such functionalized TBL monomers. The subject can be a human or other mammal having or suspected of having or acquiring a viral infection, including COVID-19, SARS, influenza, ebola, rhinovirus, hepatitis B or hepatitis C, MERS, HIV, adenovirus, measles, mumps, chickenpox, or another viral infection. Preferably, the functionalized TBL monomers are administered as an injectable liquid formulation or as an aerosol formulation for direct intrapulmonary administration, wherein the monomers self-assemble within the subject's body to form biodegradable nanostructures with antiviral activity. Alternatively, the monomers can be pre-assembled to form nanostructures prior to administration.

EXAMPLES

Example 1. Inhibition of Infection of Mammalian Cells by Pseudovirus Expressing SARS-CoV-2 Spike Protein

[0030] Screening studies confirmed binding of TBLs functionalized with the peptide SADE (SEQ ID NO:2) as targeting moiety to the heat-inactivated SARS-CoV-2 spike (S) protein. Binding affinity for SARS-CoV-2 envelope (E) protein by the SADE (SEQ ID NO:2) peptide was also indicated, suggesting that it would serve as a strong targeting moiety, even in the presence of mutations of the S protein. Scrambling of the amino acid sequence of SADE (SEQ ID NO:2) eliminated the binding affinity. Other peptide sequences that were identified as binding SARS-CoV-2 S protein were SASD (SEQ ID NO:7), SASE (SEQ ID NO:8), and SACD (SEQ ID NO:9).

[0031] The objective of the present in vitro experiments was to determine the ability of the same TBLs to passivate infection of mammalian cells from a pseudo SARS-CoV-2 virus. The pseudovirus was supplied by Creative Diagnostics. Results of this in vitro study showed that TBLs functionalized with SADE (SEQ ID NO:2) (i.e., the TBS monomer of Formula 1 wherein L=SADE (SEQ ID NO:2) peptide, no further targeting moieties) can passivate the SARS-CoV-2 pseudovirus and inhibit its ability to infect mammalian cells.

[0032] A lentiviral SARS-CoV-2 pseudovirus was used for the study. While live SARS-CoV-2 has to be handled under biosafety level 3 conditions, which has hindered the development of vaccines and therapeutics, pseudoviruses are useful virological tools because of their safety and versatility, because the pseudovirus is restricted to a single round of replication and can be handled using BSL-2 containment practices. The pseudovirus expressed GFP in infected cells, allowing infection to be measured with a fluorimeter. The pseudotyped Luciferase/GFP rSARS-CoV-2 displayed antigenically correct spike protein (Wuhan-Hu-1 strain or D614G mutant) pseudotyped on replication-incompetent virus particles that contain a heterologous lentiviral (HIV) core and were capable of a single round of infection. Pseudotyped Luciferase/GFP rSARS-CoV-2 Spike were produced in HEK-293T cells using three separate plasmids (see FIG. 3), and encoded the spike protein, a lentiviral gag polyprotein, and the GFP reporter gene.

[0033] HEK293T cells were used for transfection by the pseudovirus. This cell line is constructed by transduction of human angiotensin I converting enzyme 2 (ACE2) into HEK293T cells, followed by stable cell selection. This cell line can be used for in vitro screening and characterization of drug candidates against SARS-CoV-2 because it expresses ACE2 which serves as the host receptor for SARS-CoV-2.

[0034] TBLs functionalized with SADE (SEQ ID NO:2) were added at various concentrations (from 0 to 0.001 mg/ml) to selected concentrations of a SARS-CoV-2 pseudovirus (10 to 10.sup.6 copies/.mu.L) added to HEK293T cells seeded at 10.sup.4 cells per well. Standard cell culture medium (DMEM+10% FBS) was added to the wells. The TBLs were then allowed to interact with the pseudovirus and cells for periods of time from 15 minutes to 4 hours under standard incubator conditions. After the prescribed time period, the samples were analyzed using a fluorimeter. All experiments were conducted in triplicate and repeated at three different time periods with appropriate controls, including no TBLs, no cells, and no pseudovirus. Differences between fluorescence intensity were assessed using ANOVA and student's t test with p<0.01 considered statistically significant.

[0035] Results of this study showed that the TBLs functionalized with SADE (SEQ ID NO:2) significantly inhibited SARS-CoV-2 pseudovirus infection of the mammalian cells at all concentrations and time periods tested (see FIGS. 4A-4C). Inhibition ranged from 64% to 98%. Importantly, a pseudovirus concentration effect was observed;

[0036] when more pseudovirus was added to the cultures, more infection was found. However, no strong TBL concentration effect was not observed. All controls confirmed the validity of the experimental system.

Example 2. Inhibition of Infection of Mammalian Cells by Pseudovirus Expressing Variants of SARS-CoV-2 Spike Protein

[0037] The experiment described in Example 1 was repeated using a pseudovirus possessing the S protein of the B.1.1.7 variant (see FIGS. 5A-5C) or the 501Y.V2 variant (FIGS. 6A-6C). TBLs were functionalized with SADE (SEQ ID NO:2) (i.e., the TBS monomer of Formula 1 wherein L=SADE (SEQ ID NO:2) peptide, no further targeting moieties).

[0038] Inhibition of infection by the B.1.1.7 (UK) variant was dose dependent with respect to the amount of functionalized TBL added, and longer incubation produced somewhat greater inhibition, with the TBL effect being essentially maximum at 1 hour incubation. Inhibition ranged from 76% to 86%.

[0039] Inhibition of infection by the 501Y.V2 (South African) variant also showed dose dependency with respect to the amount of functionalized TBL. One hour incubation again produced a maximal effect, and inhibition ranged from producing from 82% to 91% inhibition of infection.

Example 3. Inhibition of Fibroblast Death from Infection by Rhinovirus or Influenza Virus

[0040] An experiment similar to that described in Example 1 was performed to test whether TBL functionalized with SADE could protect human dermal fibroblasts from death be infection with rhinovirus, influenza A virus, or influenza B virus. A fluorescent dye was used to indicate dead cells in which fluorescence intensity is proportional to the number of dead cells. The results are shown in FIG. 7 for rhinovirus infection, in FIG. 8A for influenza A infection, and in FIG. 8B for influenza B infection. Death from rhinovirus infection was inhibited by 96% to 98%, while death from influenza virus infection was inhibited by 45% to 55% for influenza A and 42% to 48% for influenza B virus over the range of TBL concentrations tested (0.001 to 1 mg/mL).

[0041] A sequence listing is provided as an ASCII text file named "Sequence-Listing-ST25-as-filed-23Jun2021-19815-0693" created on 23 Jun. 2021 and having a size of 45084 bytes. The ASCII text file is hereby incorporated by reference in the application.

REFERENCES

[0042] R. Al-Attabi, et al., Catalytic electrospun nano-composite membranes for virus capture and remediation. Separation and Purification Technology 229, 115806 (2019). [0043] H. Fenniri, et al., Helical Rosette Nanotubes: Design, Self-Assembly, and Characterization. J. Am. Chem. Soc. 123, 3854-3855 (2001). [0044] S. Kumar et al., Structural, glycosylation and antigenic variation between 2019 novel coronavirus (2019-nCoV) and SARS coronavirus (SARS-CoV). Virus Dis. doi.org/10.1007/s13337-020.00571-5, 5 Mar. 2020 [0045] S. Song, et al., Self-assembled rosette nanotubes for incorporating hydrophobic drugs in physiological environments. Int. J. Nanomedicine 6, 101-107 (2011).

Sequence CWU 1

1

29614PRTArtificial SequenceTargeting moiety 1Lys Arg Ser Arg124PRTArtificial SequenceTargeting moiety 2Ser Ala Asp Glu134PRTArtificial SequenceTargeting moiety 3Asn Gly Thr Lys144PRTArtificial SequenceTargeting moiety 4Asn Phe Thr Ile154PRTArtificial SequenceTargeting moiety 5Asn Leu Thr Thr164PRTArtificial SequenceTargeting moiety 6Asn Thr Ser Asn174PRTArtificial SequenceTargeting moiety 7Ser Ala Ser Asp184PRTArtificial SequenceTargeting moiety 8Ser Ala Ser Glu194PRTArtificial SequenceTargeting moiety 9Ser Ala Cys Asp1104PRTArtificial SequenceTargeting moiety 10Ser Ala Cys Glu1114PRTArtificial SequenceTargeting moiety 11Ser Ala Pro Asp1124PRTArtificial SequenceTargeting moiety 12Ser Ala Pro Glu1134PRTArtificial SequenceTargeting moiety 13Ser Ala Asn Asp1144PRTArtificial SequenceTargeting moiety 14Ser Ala Asn Glu1154PRTArtificial SequenceTargeting moiety 15Ser Ala Gln Asp1164PRTArtificial SequenceTargeting moiety 16Ser Ala Gln Glu1174PRTArtificial SequenceTargeting moiety 17Ser Val Ser Asp1184PRTArtificial SequenceTargeting moiety 18Ser Val Ser Glu1194PRTArtificial SequenceTargeting moiety 19Ser Val Cys Asp1204PRTArtificial SequenceTargeting moiety 20Ser Val Cys Glu1214PRTArtificial SequenceTargeting moiety 21Ser Val Pro Asp1224PRTArtificial SequenceTargeting moiety 22Ser Val Pro Glu1234PRTArtificial SequenceTargeting moiety 23Ser Val Asn Asp1244PRTArtificial SequenceTargeting moiety 24Ser Val Asn Glu1254PRTArtificial SequenceTargeting moiety 25Ser Val Gln Asp1264PRTArtificial SequenceTargeting moiety 26Ser Val Gln Glu1274PRTArtificial SequenceTargeting moiety 27Ser Leu Ser Asp1284PRTArtificial SequenceTargeting moiety 28Ser Leu Ser Glu1294PRTArtificial SequenceTargeting moiety 29Ser Leu Cys Asp1304PRTArtificial SequenceTargeting moiety 30Ser Leu Cys Glu1314PRTArtificial SequenceTargeting moiety 31Ser Leu Pro Asp1324PRTArtificial SequenceTargeting moiety 32Ser Leu Pro Glu1334PRTArtificial SequenceTargeting moiety 33Ser Leu Asn Asp1344PRTArtificial SequenceTargeting moiety 34Ser Leu Asn Glu1354PRTArtificial SequenceTargeting moiety 35Ser Leu Gln Asp1364PRTArtificial SequenceTargeting moiety 36Ser Leu Asp Glu1374PRTArtificial SequenceTargeting moiety 37Ser Met Ser Glu1384PRTArtificial SequenceTargeting moiety 38Ser Met Ser Asp1394PRTArtificial SequenceTargeting moiety 39Ser Met Cys Glu1404PRTArtificial SequenceTargeting moiety 40Ser Met Cys Asp1414PRTArtificial SequenceTargeting moiety 41Ser Met Pro Asp1424PRTArtificial SequenceTargeting moiety 42Ser Met Pro Glu1434PRTArtificial SequenceTargeting moiety 43Ser Met Asn Asp1444PRTArtificial SequenceTargeting moiety 44Ser Met Asn Glu1454PRTArtificial SequenceTargeting moiety 45Ser Met Gln Asp1464PRTArtificial SequenceTargeting moiety 46Ser Met Gln Glu1474PRTArtificial SequenceTargeting moiety 47Pro Ala Ser Asp1484PRTArtificial SequenceTargeting moiety 48Pro Ala Ser Glu1494PRTArtificial SequenceTargeting moiety 49Pro Ala Cys Asp1504PRTArtificial SequenceTargeting moiety 50Pro Ala Cys Glu1514PRTArtificial SequenceTargeting moiety 51Pro Ala Pro Asp1524PRTArtificial SequenceTargeting moiety 52Pro Ala Pro Glu1534PRTArtificial SequenceTargeting moiety 53Pro Ala Asn Asp1544PRTArtificial SequenceTargeting moiety 54Pro Ala Asn Glu1554PRTArtificial SequenceTargeting moiety 55Pro Ala Gln Asp1564PRTArtificial SequenceTargeting moiety 56Pro Ala Gln Glu1574PRTArtificial SequenceTargeting moiety 57Pro Val Ser Asp1584PRTArtificial SequenceTargeting moiety 58Pro Val Ser Glu1594PRTArtificial SequenceTargeting moiety 59Pro Val Cys Asp1604PRTArtificial SequenceTargeting moiety 60Pro Val Cys Glu1614PRTArtificial SequenceTargeting moiety 61Pro Val Pro Asp1624PRTArtificial SequenceTargeting moiety 62Pro Val Pro Glu1634PRTArtificial SequenceTargeting moiety 63Pro Val Asn Asp1644PRTArtificial SequenceTargeting moiety 64Pro Val Asn Glu1654PRTArtificial SequenceTargeting moiety 65Pro Val Gln Asp1664PRTArtificial SequenceTargeting moiety 66Pro Val Gln Glu1674PRTArtificial SequenceTargeting moiety 67Pro Leu Ser Asp1684PRTArtificial SequenceTargeting moiety 68Pro Leu Ser Glu1694PRTArtificial SequenceTargeting moiety 69Pro Leu Cys Asp1704PRTArtificial SequenceTargeting moiety 70Pro Leu Cys Glu1714PRTArtificial SequenceTargeting moiety 71Pro Leu Pro Asp1724PRTArtificial SequenceTargeting moiety 72Pro Leu Pro Glu1734PRTArtificial SequenceTargeting moiety 73Pro Leu Asn Asp1744PRTArtificial SequenceTargeting moiety 74Pro Leu Asn Glu1754PRTArtificial SequenceTargeting moiety 75Pro Leu Gln Asp1764PRTArtificial SequenceTargeting moiety 76Pro Leu Gln Glu1774PRTArtificial SequenceTargeting moiety 77Pro Met Ser Asp1784PRTArtificial SequenceTargeting moiety 78Pro Met Ser Glu1794PRTArtificial SequenceTargeting moiety 79Pro Met Cys Asp1804PRTArtificial SequenceTargeting moiety 80Pro Met Cys Glu1814PRTArtificial SequenceTargeting moiety 81Cys Ala Ser Asp1824PRTArtificial SequenceTargeting moiety 82Cys Ala Ser Glu1834PRTArtificial SequenceTargeting moiety 83Cys Ala Cys Asp1844PRTArtificial SequenceTargeting moiety 84Cys Ala Cys Glu1854PRTArtificial SequenceTargeting moiety 85Cys Ala Pro Asp1864PRTArtificial SequenceTargeting moiety 86Cys Ala Pro Glu1874PRTArtificial SequenceTargeting moiety 87Cys Ala Asn Asp1884PRTArtificial SequenceTargeting moiety 88Cys Ala Asn Glu1894PRTArtificial SequenceTargeting moiety 89Cys Ala Gln Asp1904PRTArtificial SequenceTargeting moiety 90Cys Ala Gln Glu1914PRTArtificial SequenceTargeting moiety 91Cys Val Ser Asp1924PRTArtificial SequenceTargeting moiety 92Cys Val Ser Glu1934PRTArtificial SequenceTargeting moiety 93Cys Val Cys Asp1944PRTArtificial SequenceTargeting moiety 94Cys Val Cys Glu1954PRTArtificial SequenceTargeting moiety 95Cys Val Pro Asp1964PRTArtificial SequenceTargeting moiety 96Cys Val Pro Glu1974PRTArtificial SequenceTargeting moiety 97Cys Val Asn Asp1984PRTArtificial SequenceTargeting moiety 98Cys Val Asn Glu1994PRTArtificial SequenceTargeting moiety 99Cys Val Gln Asp11004PRTArtificial SequenceTargeting moiety 100Cys Val Gln Glu11014PRTArtificial SequenceTargeting moiety 101Cys Leu Ser Asp11024PRTArtificial SequenceTargeting moiety 102Cys Leu Ser Glu11034PRTArtificial SequenceTargeting moiety 103Cys Leu Cys Asp11044PRTArtificial SequenceTargeting moiety 104Cys Leu Cys Glu11054PRTArtificial SequenceTargeting moiety 105Cys Leu Pro Asp11064PRTArtificial SequenceTargeting moiety 106Cys Leu Pro Glu11074PRTArtificial SequenceTargeting moiety 107Cys Leu Asn Asp11084PRTArtificial SequenceTargeting moiety 108Cys Leu Asn Glu11094PRTArtificial SequenceTargeting moiety 109Cys Leu Gln Asp11104PRTArtificial SequenceTargeting moiety 110Cys Leu Gln Glu11114PRTArtificial SequenceTargeting moiety 111Cys Met Ser Asp11124PRTArtificial SequenceTargeting moiety 112Cys Met Ser Glu11134PRTArtificial SequenceTargeting moiety 113Cys Met Cys Asp11144PRTArtificial SequenceTargeting moiety 114Cys Met Ser Glu11154PRTArtificial SequenceTargeting moiety 115Cys Met Pro Asp11164PRTArtificial SequenceTargeting moiety 116Cys Met Pro Glu11174PRTArtificial SequenceTargeting moiety 117Cys Met Asn Asp11184PRTArtificial SequenceTargeting moiety 118Cys Met Asn Glu11194PRTArtificial SequenceTargeting moiety 119Cys Met Gln Asp11204PRTArtificial SequenceTargeting moiety 120Cys Met Gln Glu11214PRTArtificial SequenceTargeting moiety 121Thr Ala Ser Asp11224PRTArtificial SequenceTargeting moiety 122Thr Ala Ser Glu11234PRTArtificial SequenceTargeting moiety 123Thr Ala Cys Asp11244PRTArtificial SequenceTargeting moiety 124Thr Ala Cys Glu11254PRTArtificial SequenceTargeting moiety 125Thr Ala Pro Asp11264PRTArtificial SequenceTargeting moiety 126Thr Ala Pro Glu11274PRTArtificial SequenceTargeting moiety 127Thr Ala Asn Asp11284PRTArtificial SequenceTargeting moiety 128Thr Ala Asn Glu11294PRTArtificial SequenceTargeting moiety 129Thr Ala Gln Asp11304PRTArtificial SequenceTargeting moiety 130Thr Ala Gln Glu11314PRTArtificial SequenceTargeting moiety 131Thr Val Ser Asp11324PRTArtificial SequenceTargeting moiety 132Thr Val Ser Glu11334PRTArtificial SequenceTargeting moiety 133Thr Val Cys Asp11344PRTArtificial SequenceTargeting moiety 134Thr Val Cys Glu11354PRTArtificial SequenceTargeting moiety 135Thr Val Pro Asp11364PRTArtificial SequenceTargeting moiety 136Thr Val Pro Glu11374PRTArtificial SequenceTargeting moiety 137Thr Val Asn Asp11384PRTArtificial SequenceTargeting moiety 138Thr Val Asn Glu11394PRTArtificial SequenceTargeting moiety 139Thr Val Gln Asp11404PRTArtificial SequenceTargeting moiety 140Thr Val Gln Glu11414PRTArtificial SequenceTargeting moiety 141Thr Leu Ser Asp11424PRTArtificial SequenceTargeting moiety 142Thr Leu Ser Glu11434PRTArtificial SequenceTargeting moiety 143Thr Leu Cys Asp11444PRTArtificial SequenceTargeting moiety 144Thr Leu Cys Glu11454PRTArtificial SequenceTargeting moiety 145Thr Leu Pro Asp11464PRTArtificial SequenceTargeting moiety 146Thr Leu Pro Glu11474PRTArtificial SequenceTargeting moiety 147Thr Leu Asn Asp11484PRTArtificial SequenceTargeting moiety 148Thr Leu Asn Glu11494PRTArtificial SequenceTargeting moiety 149Thr Leu Gln Asp11504PRTArtificial SequenceTargeting moiety 150Thr Leu Gln Glu11514PRTArtificial SequenceTargeting moiety 151Thr Met Ser Asp11524PRTArtificial SequenceTargeting moiety 152Thr Met Ser Glu11534PRTArtificial SequenceTargeting moiety 153Thr Met Cys Asp11544PRTArtificial SequenceTargeting moiety 154Thr Met Cys Glu11554PRTArtificial SequenceTargeting moiety 155Thr Met Pro Asp11564PRTArtificial SequenceTargeting moiety 156Thr Met Pro Glu11574PRTArtificial SequenceTargeting moiety 157Thr Met Asn Asp11584PRTArtificial SequenceTargeting moiety 158Thr Met Asn Glu11594PRTArtificial SequenceTargeting moiety 159Thr Met Gln Asp11604PRTArtificial SequenceTargeting moiety 160Thr Met Gln Glu11614PRTArtificial SequenceTargeting moiety 161Gln Ala Ser Asp11624PRTArtificial SequenceTargeting moiety 162Gln Ala Ser Glu11634PRTArtificial SequenceTargeting moiety 163Gln Val Cys Asp11644PRTArtificial SequenceTargeting moiety 164Gln Val Cys Glu11654PRTArtificial SequenceTargeting moiety 165Gln Val Pro Asp11664PRTArtificial SequenceTargeting moiety 166Gln Val Pro Glu11674PRTArtificial SequenceTargeting moiety 167Gln Val Asn Asp11684PRTArtificial SequenceTargeting moiety 168Gln Val Asn Glu11694PRTArtificial SequenceTargeting moiety 169Gln Val Gln Asp11704PRTArtificial SequenceTargeting moiety 170Gln Val Gln Glu11714PRTArtificial SequenceTargeting moiety 171Gln Leu Ser Asp11724PRTArtificial SequenceTargeting moiety 172Gln Leu Ser Glu11734PRTArtificial SequenceTargeting moiety 173Gln Leu Cys Asp11744PRTArtificial SequenceTargeting moiety 174Gln Leu Cys Glu11754PRTArtificial SequenceTargeting moiety 175Gln Leu Pro Asp11764PRTArtificial SequenceTargeting moiety 176Gln Leu Pro Glu11774PRTArtificial SequenceTargeting moiety 177Gln Leu Asn Asp11784PRTArtificial SequenceTargeting moiety 178Gln Leu Asn Glu11794PRTArtificial SequenceTargeting moiety 179Gln Leu Gln Asp11804PRTArtificial SequenceTargeting moiety 180Gln Leu Gln Glu11814PRTArtificial SequenceTargeting moiety 181Gln Met Ser Asp11824PRTArtificial SequenceTargeting moiety 182Gln Met Ser Glu11834PRTArtificial SequenceTargeting moiety 183Gln Met Cys Asp11844PRTArtificial SequenceTargeting moiety 184Gln Met Cys Glu11854PRTArtificial SequenceTargeting moiety 185Gln Met Pro Asp11864PRTArtificial SequenceTargeting moiety 186Gln Met Pro Glu11874PRTArtificial SequenceTargeting moiety 187Gln Met Asn Asp11884PRTArtificial SequenceTargeting moiety 188Gln Met Asn Glu11894PRTArtificial SequenceTargeting moiety 189Gln Met Gln Asp11904PRTArtificial SequenceTargeting moiety 190Gln Met Gln Glu11914PRTArtificial SequenceTargeting moiety 191Met Ile His Ser11924PRTArtificial SequenceTargeting moiety 192Ala Ile His Ser11934PRTArtificial SequenceTargeting moiety 193Val Ile His Ser11944PRTArtificial SequenceTargeting moiety 194Ile Ile His Ser11954PRTArtificial SequenceTargeting moiety 195Leu Ile His Ser11964PRTArtificial SequenceTargeting moiety 196Phe Ile His Ser11974PRTArtificial SequenceTargeting moiety 197Tyr Ile His Ser11984PRTArtificial SequenceTargeting moiety 198Trp Ile His Ser11994PRTArtificial SequenceTargeting moiety 199Met Ala His Ser12004PRTArtificial SequenceTargeting moiety 200Met Val His Ser12014PRTArtificial SequenceTargeting moiety 201Met Leu His Ser12024PRTArtificial SequenceTargeting moiety 202Met Met His Ser12034PRTArtificial SequenceTargeting moiety 203Met Phe His Ser12044PRTArtificial SequenceTargeting moiety 204Met Tyr His Ser12054PRTArtificial SequenceTargeting moiety 205Met Trp His Ser12064PRTArtificial SequenceTargeting moiety 206Ala Ile Arg Ser12074PRTArtificial SequenceTargeting moiety 207Ala Ile Arg Lys12084PRTArtificial SequenceTargeting moiety 208Ala Ile Asp Lys12094PRTArtificial SequenceTargeting moiety 209Ala Ile Glu Lys12104PRTArtificial SequenceTargeting moiety 210Met Ile His Thr12114PRTArtificial SequenceTargeting moiety 211Met Ile His Asn12124PRTArtificial SequenceTargeting moiety 212Met Ile His Gln12134PRTArtificial SequenceTargeting moiety 213Ala Ser Cys Ser12144PRTArtificial SequenceTargeting moiety 214Ala Thr Cys Ser12154PRTArtificial SequenceTargeting moiety 215Ala Asn Cys Ser12164PRTArtificial SequenceTargeting moiety 216Ala Gln Cys Ser12174PRTArtificial SequenceTargeting moiety 217Ala Val Cys Ser12184PRTArtificial SequenceTargeting moiety 218Val Ser Cys Ser12194PRTArtificial SequenceTargeting moiety 219Val Thr Cys Ser12204PRTArtificial SequenceTargeting moiety 220Val Asn Cys Ser12214PRTArtificial SequenceTargeting moiety 221Val Gln Cys Ser12224PRTArtificial SequenceTargeting moiety 222Val Val Cys Ser12234PRTArtificial SequenceTargeting moiety 223Ile Ser Cys Ser12244PRTArtificial SequenceTargeting moiety 224Ile Thr Cys Ser12254PRTArtificial SequenceTargeting moiety 225Ile Asn Cys Ser12264PRTArtificial SequenceTargeting moiety 226Ile Gln Cys Ser12274PRTArtificial SequenceTargeting moiety 227Ile Val Cys Ser12284PRTArtificial SequenceTargeting moiety 228Leu Ser Cys Ser12294PRTArtificial SequenceTargeting moiety 229Leu Thr Cys Ser12304PRTArtificial SequenceTargeting moiety 230Leu Asn Cys Ser12314PRTArtificial SequenceTargeting moiety 231Leu Gln Cys Ser12324PRTArtificial SequenceTargeting moiety 232Met Ser Cys Ser12334PRTArtificial SequenceTargeting moiety 233Met Thr Cys Ser12344PRTArtificial SequenceTargeting moiety 234Met Asn Cys Ser12354PRTArtificial SequenceTargeting moiety 235Met Gln Cys Ser12364PRTArtificial SequenceTargeting moiety 236Met Val Cys Ser12374PRTArtificial SequenceTargeting moiety 237Phe Ser Cys Ser12384PRTArtificial SequenceTargeting moiety 238Phe Thr Cys Ser12394PRTArtificial SequenceTargeting moiety 239Phe Asn Cys Ser12404PRTArtificial SequenceTargeting moiety 240Phe Gln Cys Ser12414PRTArtificial SequenceTargeting moiety 241Phe Val Cys Ser12424PRTArtificial SequenceTargeting moiety 242Tyr Ser Cys Ser12434PRTArtificial SequenceTargeting moiety 243Tyr Thr Cys Ser12444PRTArtificial SequenceTargeting moiety 244Tyr Asn Cys Ser12454PRTArtificial SequenceTargeting moiety 245Tyr Gln Cys Ser12464PRTArtificial SequenceTargeting moiety 246Tyr Val Cys Ser12474PRTArtificial SequenceTargeting moiety 247Trp Ser Cys Ser12484PRTArtificial SequenceTargeting moiety 248Trp Thr Cys Ser12494PRTArtificial SequenceTargeting moiety 249Trp Asn Cys Ser12504PRTArtificial SequenceTargeting moiety 250Trp Gln Cys Ser12514PRTArtificial SequenceTargeting moiety 251Trp Val Cys

Ser12524PRTArtificial SequenceTargeting moiety 252Met Gly Ala Gln12534PRTArtificial SequenceTargeting moiety 253Ala Gly Ala Gln12544PRTArtificial SequenceTargeting moiety 254Val Gly Ala Gln12554PRTArtificial SequenceTargeting moiety 255Ile Gly Ala Gln12564PRTArtificial SequenceTargeting moiety 256Leu Gly Ala Gln12574PRTArtificial SequenceTargeting moiety 257Phe Gly Ala Gln12584PRTArtificial SequenceTargeting moiety 258Tyr Gly Ala Gln12594PRTArtificial SequenceTargeting moiety 259Trp Gly Ala Gln12604PRTArtificial SequenceTargeting moiety 260Ala Cys Ala Gln12614PRTArtificial SequenceTargeting moiety 261Val Cys Ala Gln12624PRTArtificial SequenceTargeting moiety 262Ile Cys Ala Gln12634PRTArtificial SequenceTargeting moiety 263Leu Cys Ala Gln12644PRTArtificial SequenceTargeting moiety 264Met Cys Ala Gln12654PRTArtificial SequenceTargeting moiety 265Phe Cys Ala Gln12664PRTArtificial SequenceTargeting moiety 266Tyr Cys Ala Gln12674PRTArtificial SequenceTargeting moiety 267Trp Cys Ala Gln12684PRTArtificial SequenceTargeting moiety 268Ala Pro Ala Gln12694PRTArtificial SequenceTargeting moiety 269Val Pro Ala Gln12704PRTArtificial SequenceTargeting moiety 270Ile Pro Ala Gln12714PRTArtificial SequenceTargeting moiety 271Leu Pro Ala Gln12724PRTArtificial SequenceTargeting moiety 272Phe Pro Ala Gln12734PRTArtificial SequenceTargeting moiety 273Tyr Pro Ala Gln12744PRTArtificial SequenceTargeting moiety 274Trp Pro Ala Gln12754PRTArtificial SequenceTargeting moiety 275Ala Gly Val Gln12764PRTArtificial SequenceTargeting moiety 276Val Gly Val Gln12774PRTArtificial SequenceTargeting moiety 277Ile Gly Val Gln12784PRTArtificial SequenceTargeting moiety 278Leu Gly Val Gln12794PRTArtificial SequenceTargeting moiety 279Phe Gly Val Gln12804PRTArtificial SequenceTargeting moiety 280Tyr Gly Val Gln12814PRTArtificial SequenceTargeting moiety 281Trp Gly Val Gln12824PRTArtificial SequenceTargeting moiety 282Ala Cys Val Gln12834PRTArtificial SequenceTargeting moiety 283Val Cys Val Gln12844PRTArtificial SequenceTargeting moiety 284Ile Cys Val Gln12854PRTArtificial SequenceTargeting moiety 285Leu Cys Val Gln12864PRTArtificial SequenceTargeting moiety 286Met Cys Val Gln12874PRTArtificial SequenceTargeting moiety 287Phe Cys Val Gln12884PRTArtificial SequenceTargeting moiety 288Tyr Cys Val Gln12894PRTArtificial SequenceTargeting moiety 289Trp Cys Val Gln12904PRTArtificial SequenceTargeting moiety 290Ala Pro Val Gln12914PRTArtificial SequenceTargeting moiety 291Val Pro Val Gln12924PRTArtificial SequenceTargeting moiety 292Ile Pro Val Gln12934PRTArtificial SequenceTargeting moiety 293Leu Pro Val Gln12944PRTArtificial SequenceTargeting moiety 294Phe Pro Val Gln12954PRTArtificial SequenceTargeting moiety 295Tyr Pro Val Gln12964PRTArtificial SequenceTargeting moiety 296Trp Pro Val Gln1

Claims

1. An antiviral composition comprising a plurality of functionalized twin base linker (TBL) molecules having the general structure ##STR00004## wherein the twin bases comprise a structure according to Formula 1 ##STR00005## wherein L is the linker and comprises carbon, nitrogen, and/or oxygen atoms and has a chain length from about 4 to about 20 atoms; wherein the peptide moiety contains from about 2 to about 20 L- and/or D-amino acids; and wherein optionally one or more targeting moieties are covalently linked to the peptide, the targeting moieties capable of specifically binding a surface-accessible protein of a virus, thereby deactivating the virus, or wherein the targeting moieties are absent, and the peptide moiety is capable of specifically binding a surface-accessible protein of a virus, thereby deactivating the virus.

2. The antiviral composition of claim 1, wherein the targeting moieties are present and are selected from the group consisting of antibodies, aptamers, and peptides.

3. The antiviral composition of claim 1, wherein the peptide comprises one or more amino acids that are positively charged at pH 7 and/or one or more amino acids that are negatively charged at pH 7.

4. The antiviral composition of claim 1, wherein the functionalized TBL molecules comprise one or more targeting moieties covalently attached to the peptide moiety, and wherein the one or more targeting moieties are peptides, each peptide having an amino acid sequence that is distinct from that of the peptide moiety.

5. The antiviral composition of claim 1, wherein the functionalized TBL molecules comprise a peptide moiety or a targeting moiety that binds to a virus spike protein, a virus envelope protein, or both.

6. The antiviral composition of claim 5, wherein the peptide moiety or a targeting moiety comprise a peptide selected from the group consisting of SADE (SEQ ID NO:2), SASD (SEQ ID NO:7), SASE (SEQ ID NO:8), and SACD (SEQ ID NO:9).

7. The antiviral composition of claim 1, comprising functionalized TBL molecules in monomeric form.

8. The antiviral composition of claim 1, comprising functionalized TBL molecules in form of a supramolecular assembly.

9. The antiviral composition of claim 1, wherein the peptide moiety or the targeting moieties bind to a protein of SARS-CoV-2 virus.

10. The antiviral composition of claim 9, wherein the peptide moiety or the targeting moieties bind to S protein of SARS-CoV-2 virus.

11. The antiviral composition of claim 10, wherein the peptide moiety or the targeting moieties also bind to E protein of SARS-CoV-2 virus.

12. The antiviral composition of claim 1, wherein the functionalized TBL molecules, or a supramolecular assembly comprising the functionalized TBL molecules, is capable of inhibiting entry of the virus into a mammalian cell.

13. The antiviral composition of claim 1, wherein the functionalized TBL molecules, or a supramolecular assembly comprising the functionalized TBL molecules, is capable of inhibiting death of mammalian cells infected by the virus.

14. The antiviral composition of claim 1, wherein the composition is for use in treating or preventing a viral infection.

15. The antiviral composition of claim 14, wherein the viral infection is caused by a virus selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, an adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus.

16. The antiviral composition of claim 14, wherein the composition is for use in treating or preventing two or more viral infections selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, an adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus.

17. The antiviral composition of claim 16, wherein the composition is for treating or preventing infection by SARS CoV-2, influenza A virus, influenza B virus, and rhinovirus.

18. A method to aid in treating or preventing a viral infection, the method comprising administering the antiviral composition of claim 1 to a subject in need thereof.

19. The method of claim 18, wherein the viral infection is caused by a virus selected from the group consisting of a corona virus, SARS-CoV-2, influenza A virus, influenza B virus, an ebola virus, HIV, adenovirus, a rhinovirus, hepatitis B virus, hepatitis C virus, MERS virus, measles virus, mumps virus, and chickenpox virus.

20. The method of claim 19, wherein the virus is SARS-CoV-2.

21. The method of claim 18, wherein cellular entry of a virus, virus replication, and/or one or more symptoms of the viral infection are reduced or prevented in the subject.