[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of U.S. Patent Application Nos. 63/020,398 filed May 5, 2020, 63/020,796 filed May 6, 2020, and 63/022,764 filed May 11, 2020, which are herein incorporated by reference in their entirety.

[0003] REFERENCE TO A SEQUENCE LISTING SUBMITTED VIA EFS-WEB

[0004] The content of the ASCII text file of the sequence listing named

“20210504_177264_003W01_ST25” which is 84.8 kb in size was created on May 4, 2021 and electronically submitted via EFS-Web herewith the application is incorporated herein by reference in its entirety.

[0005] BACKGROUND OF THE INVENTION

[0006] 1. FIELD OF THE INVENTION

[0007] The field of the invention generally relates to compositions that inactivate, inhibit, or degrade target RNA molecules and methods of using said compositions to treat and/or inhibit diseases and infections related to the target RNA molecules.

[0008] BACKGROUND OF THE INVENTION

[0009] 1. FIELD OF THE INVENTION

[0010] The field of the invention generally relates to oligonucleotide therapeutics and methods of treating or inhibiting diseases and infections therewith.

[0011] 2. DESCRIPTION OF THE RELATED ART

[0012] A variety of diseases and infections may be treated or inhibited by disrupting the expression of a target gene ( e.g ., a mutated gene resulting in an aberrant protein or aberrant protein expression; a gene of a pathogenic organism) by, e.g., annealing an oligonucleotide to a portion of the gene. Once bound, the complex becomes a substrate for enzymatic digestion by endonucleases. In the case of an RNA target, e.g, an RNA virus such as a coronavirus, the oligonucleotide:RNA gene complex is degraded by RNA endonucleases (RNases, e.g, RNase H) thereby effectively inactivating the RNA virus.

[0013] Since December 2019, there has been an ongoing global outbreak of coronavirus disease 2019 (COVID-19). COVID-19 is caused by a highly contagious coronavirus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Because SARS-CoV-2 was a novel virus (i.e., not previously known to infect humans), there were no therapeutics that were known to effectively treat COVID-19. [0014] Thus, what is needed is a modular therapeutic in which can be readily modified to treat a given disease or infection.

[0015] SUMMARY OF THE INVENTION

[0016] In some embodiments, the present invention is directed to a modular therapeutic, which comprises (1) one or more given therapeutic oligonucleotides; and (2)(a) one or more targeting agents selected from a cell-penetrating peptide (CPP) and a receptor binding peptide, and/or (b) one or more anti-RNA agents selected from a ribonuclease (RNase) and an arogonaute protein. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP and the RNase fused directly or indirectly together. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP, the RNase, and the receptor binding peptide fused directly or indirectly together. In some embodiments, the fusions are via a peptide linker, preferably a flexible linker such as a glycine rich linker. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID

NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID

NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID

NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID

NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID

NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID

NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID

NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID

NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID

NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the arogonaute protein of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%,

92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an RNase having 90%, 91%,

92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%,

96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a fusion protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 116 or SEQ ID NO: 119. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 116. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 119. In some embodiments, the length of the one or more given therapeutic oligonucleotides is about 15-30 nucleotides, about 16-29 nucleotides, about 17-28 nucleotides, about 18-27 nucleotides, about 19-26 nucleotides, or about 20-25 nucleotides. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. In some embodiments, the one or more given therapeutic oligonucleotides is a coronavirus oligonucleotide. In some embodiments, the one or more given therapeutic oligonucleotides has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a region within a sequence selected from SEQ ID NO: 1, the complement of SEQ ID NO: 1, the reverse sequence of SEQ ID NO: 1, the reverse complement of SEQ ID NO:

1, SEQ ID NO: 2, the complement of SEQ ID NO: 2, the reverse sequence of SEQ ID NO: 2, the reverse complement of SEQ ID NO: 2, SEQ ID NO: 3, the complement of SEQ ID NO: 3, the reverse sequence of SEQ ID NO: 3, the reverse complement of SEQ ID NO: 3, SEQ ID NO: 4, the complement of SEQ ID NO: 4, the reverse sequence of SEQ ID NO: 4, the reverse complement of SEQ ID NO: 4, SEQ ID NO: 5, the complement of SEQ ID NO: 5, the reverse sequence of SEQ ID NO: 5, and the reverse complement of SEQ ID NO: 5. In some embodiments, the one or more given therapeutic oligonucleotides is substantially identical to a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO:

19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO:

24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO:

29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO:

34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO:

39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, and SEQ ID NO: 44. In some embodiments, the sequence of the one or more given therapeutic oligonucleotides is SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44. In some embodiments, the one or more given therapeutic oligonucleotides is covalently attached directly or indirectly to a targeting agent, which may be the one or more targeting agents.

[0017] In some embodiments, the present invention is directed to a method of inactivating a target gene in a cell or in a subject, which comprises administering the modular therapeutic as disclosed herein, e.g., in the preceding paragraphs, to the cell or the subject, wherein the sequence of the one or more given therapeutic oligonucleotides is substantially identical the target gene or its complement, reverse sequence, or reverse complement. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. In some embodiments, the target gene is exogenous to the subject or cell being treated. In some embodiments, the target gene is endogenous to the subject or cell being treated. In some embodiments, the target gene is of a virus (e.g, an Ebolavirus spp., an Influenzavirus spp., a coronavirus, etc.) or of a microorganism such as a bacteria or fungus (e.g., Mycobacterium spp., Aspergillus spp., etc.). In some embodiments, the target gene is one that is abnormally expressed. In some embodiments, expression of the target gene results in a disease, e.g, a metabolic disease such as chronic obstructive pulmonary disease or a cancer such as lung cancer. In some embodiments, the target gene is RNA. In some embodiments, the target gene is an RNA gene of a given RNA virus. In some embodiments, the target gene is an mRNA transcript.

[0018] In some embodiments, the present invention is directed to a method of preventing or inhibiting a coronavirus from infecting a cell or a subject, which comprises administering to the cell or the subject a modular therapeutic as disclosed herein, wherein the one or more given therapeutic oligonucleotides is a coronavirus oligonucleotide. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a region within a sequence selected from SEQ ID NO: 1, the complement of SEQ ID NO: 1, the reverse sequence of SEQ ID NO: 1, the reverse complement of SEQ ID NO: 1, SEQ ID NO: 2, the complement of SEQ ID NO: 2, the reverse sequence of SEQ ID NO: 2, the reverse complement of SEQ ID NO: 2, SEQ ID NO: 3, the complement of SEQ ID NO: 3, the reverse sequence of SEQ ID NO: 3, the reverse complement of SEQ ID NO: 3, SEQ ID NO: 4, the complement of SEQ ID NO: 4, the reverse sequence of SEQ ID NO: 4, the reverse complement of SEQ ID NO: 4, SEQ ID NO: 5, the complement of SEQ ID NO: 5, the reverse sequence of SEQ ID NO: 5, and the reverse complement of SEQ ID NO: 5. In some embodiments, the coronavirus oligonucleotide is substantially identical to a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO:

22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO:

27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO:

32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO:

37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO:

42, SEQ ID NO: 43, and SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is covalently attached directly or indirectly to a targeting agent, which may be the one or more targeting agents. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP and the RNase fused directly or indirectly together. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP, the RNase, and the receptor binding peptide fused directly or indirectly together. In some embodiments, the fusions are via a peptide linker, preferably a flexible linker such as a glycine rich linker. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:

104, SEQ ID NO: 98, or SEQ ID NO: 101. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO:

105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the arogonaute protein of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an RNase having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,

99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85,

SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90,

SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95,

SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100,

SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a fusion protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 116 or SEQ ID NO: 119. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 116. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 119. In some embodiments, the coronavirus is a SARS-CoV-2 virus.

[0019] In some embodiments, the present invention is directed to a method of treating a COVID disease in a subject or inhibiting the development of the COVID disease in the subject, which comprises administering to the subject a modular therapeutic as disclosed herein, wherein the one or more given therapeutic oligonucleotides is a coronavirus oligonucleotide. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a region within a sequence selected from SEQ ID NO: 1, the complement of SEQ ID NO: 1, the reverse sequence of SEQ ID NO: 1, the reverse complement of SEQ ID NO: 1, SEQ ID NO: 2, the complement of SEQ ID NO: 2, the reverse sequence of SEQ ID NO: 2, the reverse complement of SEQ ID NO: 2, SEQ ID NO: 3, the complement of SEQ ID NO: 3, the reverse sequence of SEQ ID NO: 3, the reverse complement of SEQ ID NO: 3, SEQ ID NO: 4, the complement of SEQ ID NO: 4, the reverse sequence of SEQ ID NO: 4, the reverse complement of SEQ ID NO: 4, SEQ ID NO: 5, the complement of SEQ ID NO: 5, the reverse sequence of SEQ ID NO: 5, and the reverse complement of SEQ ID NO: 5. In some embodiments, the coronavirus oligonucleotide is substantially identical to a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO:

22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO:

27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO:

32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO:

37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO:

42, SEQ ID NO: 43, and SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is covalently attached directly or indirectly to a targeting agent, which may be the one or more targeting agents. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP and the RNase fused directly or indirectly together. In some embodiments, the modular therapeutic comprises a fusion protein comprising the CPP, the RNase, and the receptor binding peptide fused directly or indirectly together. In some embodiments, the fusions are via a peptide linker, preferably a flexible linker such as a glycine rich linker. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80. In some embodiments, the CPP of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104. In some embodiments, the receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:

104, SEQ ID NO: 98, or SEQ ID NO: 101. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO:

105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the arogonaute protein of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an RNase having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,

99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80; a receptor binding peptide having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88, SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93, SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an RNase of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the modular therapeutic comprises a CPP having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80; a receptor binding peptide of the modular therapeutic has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101; and an arogonaute protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the modular therapeutic comprises a fusion protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 116 or SEQ ID NO: 119. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 116. In some embodiments, the modular therapeutic comprises a fusion protein having SEQ ID NO: 119. In some embodiments, the coronavirus is a SARS-CoV-2 virus.

[0020] In some embodiments, the present invention is directed to a fusion protein comprising an amino acid sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%,

97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 116 or SEQ ID NO: 119.

[0021] In some embodiments, the present invention is directed to a kit which comprises one or more given therapeutic oligonucleotides packaged together with (a) one or more targeting agents selected from a cell-penetrating peptide (CPP) and a receptor binding peptide, and/or (b) one or more anti-RNA agents selected from a ribonuclease (RNase) and an arogonaute protein. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. In some embodiments, the CPP and the RNase are fused directly or indirectly together. In some embodiments, the CPP, the RNase, and the receptor binding peptide are fused directly or indirectly together. In some embodiments, the fusions are via a peptide linker, preferably a flexible linker such as a glycine rich linker. In some embodiments, the CPP has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 45, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57,

SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62,

SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67,

SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72,

SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77,

SEQ ID NO: 78, SEQ ID NO: 79, and SEQ ID NO: 80. In some embodiments, the CPP has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 80. In some embodiments, the receptor binding peptide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 81, SEQ ID NO: 82, SEQ ID NO: 83,

SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86, SEQ ID NO: 87, SEQ ID NO: 88,

SEQ ID NO: 89, SEQ ID NO: 90, SEQ ID NO: 91, SEQ ID NO: 92, SEQ ID NO: 93,

SEQ ID NO: 94, SEQ ID NO: 95, SEQ ID NO: 96, SEQ ID NO: 97, SEQ ID NO: 98,

SEQ ID NO: 99, SEQ ID NO: 100, SEQ ID NO: 101, SEQ ID NO: 102, SEQ ID NO: 103, and SEQ ID NO: 104. In some embodiments, the receptor binding peptide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 104, SEQ ID NO: 98, or SEQ ID NO: 101. In some embodiments, the RNase has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to a sequence selected from the group consisting of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, and SEQ ID NO: 110. In some embodiments, the RNase has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,

98%, 99%, or 100% sequence identity to SEQ ID NO: 109 or SEQ ID NO: 110. In some embodiments, the arogonaute protein has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 111. In some embodiments, the kit comprises a fusion protein comprising an amino acid sequence having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 116 or SEQ ID NO: 119. In some embodiments, the one or more given therapeutic oligonucleotides is a coronavirus oligonucleotide. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a region within a sequence selected from SEQ ID NO: 1, the complement of SEQ ID NO: 1, the reverse sequence of SEQ ID NO: 1, the reverse complement of SEQ ID NO: 1, SEQ ID NO: 2, the complement of SEQ ID NO: 2, the reverse sequence of SEQ ID NO: 2, the reverse complement of SEQ ID NO: 2, SEQ ID NO: 3, the complement of SEQ ID NO: 3, the reverse sequence of SEQ ID NO: 3, the reverse complement of SEQ ID NO: 3, SEQ ID NO: 4, the complement of SEQ ID NO: 4, the reverse sequence of SEQ ID NO: 4, the reverse complement of SEQ ID NO: 4, SEQ ID NO: 5, the complement of SEQ ID NO: 5, the reverse sequence of SEQ ID NO: 5, and the reverse complement of SEQ ID NO: 5. In some embodiments, the coronavirus oligonucleotide is substantially identical to a sequence selected from the group consisting of SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO:

17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO:

22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO:

27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO:

32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO:

37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO:

42, SEQ ID NO: 43, and SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, or SEQ ID NO: 44. In some embodiments, the coronavirus oligonucleotide is covalently attached directly or indirectly to a targeting agent, which may be the one or more targeting agents.

[0022] In some embodiments, the present invention is directed to the use of a modular therapeutic as described herein.

[0023] In some embodiments, the present invention is directed to the combined use of a modular therapeutic and a coronavirus oligonucleotide as described herein to treat or prevent infection by a coronavirus or treat a COVID disease in a subject.

[0024] Both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide further explanation of the invention as claimed. The accompanying drawings are included to provide a further understanding of the invention and are incorporated in and constitute part of this specification, illustrate several embodiments of the invention, and together with the description explain the principles of the invention.

[0025] DESCRIPTION OF THE DRAWINGS

[0026] This invention is further understood by reference to the drawings wherein:

[0027] Figure l is a graph showing that anti-RNA agents fused to one or more targeting agents ( e.g ., a CPP-RNase fusion and an ACE2 RBP-CPP-RNase fusion) exhibit nucleic acid digestion-degradation activity against therapeutic oligonucleotide: target gene complexes.

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] Disclosed herein is a modular therapeutic that can be readily modified to target and treat or inhibit a given disease or infection, including those caused by novel viruses like SARS-CoV-2. The modular therapeutic comprises the following components: (1) one or more given therapeutic oligonucleotides, and (2A) one or more targeting agents and/or (2B) one or more anti-RNA agents. In some embodiments, the modular therapeutic is a composition, wherein the components are provided as a mixture. In some embodiments, the modular therapeutic is a fusion, wherein the components are linked together to form a single compound. In some embodiments, the modular therapeutic is a mixture of a “free” component and a “fusion” of two or more components. For example, the “free” component may be the given therapeutic oligonucleotide and the “fusion” may be two targeting agents fused together or the one or more targeting agents fused to the anti-RNA agent. In some embodiments, the modular therapeutic is a mixture, wherein the components are provided as two or more different fusions. For example, the mixture may comprise (a) a given therapeutic oligonucleotide fused to a first targeting agent, and (b) the given therapeutic oligonucleotide fused to a second targeting agent or an anti-RNA agent. When two or more components that are peptides are provided as a fusion, the peptides may be linked together via a peptide linker, preferably a flexible linker such as a glycine rich linker. In some embodiments, the one or more given therapeutic oligonucleotides and the protein portion (z.e., the one or more targeting agents and/or the one or more anti-RNA agents) are provided in a molar ratio of about 10: 1 to about 1 : 10, about 5: 1 to about 1:5, or about 1:1. [0030] (1) THERAPEUTIC OLIGONUCLEOTIDES

[0031] The “given” therapeutic oligonucleotides may be any desired nucleic acid molecule of about 15-30 nucleotides, about 16-29 nucleotides, about 17-28 nucleotides, about 18-27 nucleotides, about 19-26 nucleotides, or about 20-25 nucleotides long. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably 2'-deoxy-2'-fluoroarabino nucleic acids (FANAs). In some embodiments, the therapeutic oligonucleotide comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs.

[0032] Therapeutic oligonucleotide are selected based on a given disease or infection desired to be treated. Particularly, a therapeutic oligonucleotide is selected based on a given “target gene” the expression of which in a cell or subject is to be reduced or inhibited. The reduced or inhibited expression of the target gene in a subject will thereby treat, inhibit, and/or reduce the given disease or infection (and/or the symptoms of the given disease or infection) in the subject. The sequence of the therapeutic oligonucleotide is one that specifically hybridizes to the target gene or its complement, reverse sequence, or reverse complement. In some embodiments, the therapeutic oligonucleotides have a sequence that is substantially identical to the target gene or its complement, reverse sequence, or reverse complement. As used herein, an oligonucleotide sequence that is “substantially identical” to a reference sequence means that when the oligonucleotide sequence is optimally aligned with the reference sequence, the oligonucleotide sequence may have up to 1, 2, or 3 nucleotide differences ( e.g ., substitutions, additions, or deletions) over the comparison window. In some embodiments, therapeutic oligonucleotides include guide sequences for CRISPR gene editing techniques and siRNAs known in the art.

[0033] The target gene may be exogenous or endogenous to the subject or cell being treated. For example, the target gene may be that of a foreign virus (e.g., an Ebolavirus spp., an Influenzavirus spp., a coronavirus, etc.) or microorganism such as a bacteria or fungus (e.g. , Mycobacterium spp., Aspergillus spp., etc.). Alternatively, the target gene may be endogenous to the subject being treated. For example, the endogenous target gene may be a gene that is abnormally expressed and thereby results in, e.g, a metabolic disease such as chronic obstructive pulmonary disease, or endogenous target gene may be a mutant gene that results in, e.g, a cancer such as lung cancer. In some embodiments, the target gene is RNA. In some embodiments, the target gene is an RNA gene of a given RNA virus. In some embodiments, the target gene is an mRNA transcript.

[0034] In some embodiments, the therapeutic oligonucleotide is a coronavirus oligonucleotide. As used herein, a “coronavirus oligonucleotide” refers to a nucleic acid molecule consisting of about 15-30 nucleotides, about 16-28 nucleotides, about 17-26 nucleotides, or about 18-24 nucleotides of a coronavirus sequence or its complement, reverse sequence, or reverse complement. In some embodiments, the coronavirus oligonucleotide has a sequence that is the same as that of a portion of a coronavirus sequence or its complement, reverse sequence, or reverse complement, with up to 1, 2, or 3 nucleotide differences (e.g, substitutions, additions, or deletions). In some embodiments, the coronavirus oligonucleotide has less than about 80%, less than about 79%, less than about 78%, less than about 77%, less than about 76%, or less than about 75% sequence identity to nucleic acid sequences of the human genome and their complements, reverse sequences, or reverse complements.

[0035] In some embodiments, the coronavirus oligonucleotide does not encode an amino acid sequence that spans amino acid position 452 and/or position 501 when optimally aligned with Accession No. MN985325.1. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a portion ranging from nucleotides 21563-25384 of Accession No. MN985325.1 (SEQ ID NO: 1) or its complement, reverse sequence, or reverse complement. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a portion ranging from nucleotides 266-13468 of Accession No. MN985325.1 (SEQ ID NO: 2) or its complement, reverse sequence, or reverse complement. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity over its length to a portion ranging from nucleotides 13468- 21555 of Accession No. MN985325.1 (SEQ ID NO: 3) or its complement, reverse sequence, or reverse complement. In some embodiments, the coronavirus oligonucleotide has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,

99%, or 100% sequence identity over its length to a portion ranging from nucleotides 29558-29674 of Accession No. MN985325.1 (SEQ ID NO: 4) or its complement, reverse sequence, or reverse complement. In some embodiments, the coronavirus oligonucleotide is substantially identical to a sequence selected from the group consisting of SEQ ID NO: 5 to SEQ ID NO: 44, and the complements, reverse sequences, and reverse complements thereof. In some embodiments, the coronavirus oligonucleotide is a sequence selected from the group consisting of SEQ ID NO: 5 to SEQ ID NO: 44, and the complements, reverse sequences, and reverse complements thereof.

[0036] (2A) TARGETING AGENTS

[0037] The one or more targeting agents may be (i) a cell-penetrating peptide (CPP), and/or (ii) a receptor binding peptide.

[0038] Cell-Penetrating Peptides

[0039] The cell-penetrating peptide (CPP) may be any CPP known in the art. See e.g. ,

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US20190046652, US20200095283, US20200131231, US20200172579,

US20200316210, US20210070806, WO/2010/012850A1, WO/2013/034805A1,

WO/2017/134148A1, WO/2019/202049 Al, WO/2020/144317 Al, Xie J, etal. Front Pharmacol. 2020; 11 :697; and Habault & Poyet. Molecules. 2019; 24(5): 927, Milletti F. Drug Discovery Today. 2012; 17(15-16): 850-60, Stalmans S, etal. PLOS ONE. 2013; 8(8): e71752., and Derakhshankhah H, etal. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2018; 108: 1090-1096, which are herein incorporated by reference in their entirety.

[0040] Exemplary CPPs include cationic CPPs, amphipathic CPPs, and hydrophobic

CPPs such as Transportan (AGYLLGKINLKALAALAKKIL, SEQ ID NO: 45),

T ransportan-Control (AGYLLGKINLKALAALAKKILSTLWDTAELWQ, SEQ ID NO:

46), Transportan-NBD (AGYLLGKINLKALAALAKKILTALDWSWLQTE, SEQ ID NO: 47), Transportan-PKI (AGYLLGKINLKALAALAKKILTYADFIASGRTGRRNAI, SEQ ID NO: 48), NLS (CGYGPKKKRKVGG, SEQ ID NO: 49), C105Y (CSIPPEVKFNPFVYLI, SEQ ID NO: 50), MPG HIV-gp41/SV40 T-antigen (GALFLGFLGAAGSTMGAWSQPKKKRKV, SEQ ID NO: 51), Melittin (GIGAVLKVLTTGLPALISWIKRKRQQ, SEQ ID NO: 52), TAT (GRKKRRQRRRPPQ, SEQ ID NO: 53), TAT-Control (GRKKRRQRRRPPQSTLWDTAELWQ, SEQ ID NO: 54), TAT-NBD (GRKKRRQRRRPPQTALDWSWLQTE, SEQ ID NO: 55), TAT-PKI (GRKKRRQRRRPPQTYADFIASGRTGRRNAI, SEQ ID NO: 56), DPV6 (GRPRESGKKRKRKRLKP, SEQ ID NO: 57), R9-TAT (GRRRRRRRRRPPQ, SEQ ID NO: 58), Transportan (GWTLNSAGYLLGKINLKALAALAKKIL, SEQ ID NO: 59), gH625 (HGLASTLTRWAHYNALIRAF, SEQ ID NO: 60), Pep- 1 HIV-reverse transcriptase/S V40 T-antigen (KETWWETWWTEWSQPKKKRKV, SEQ ID NO: 61), 8- ly sines (KKKKKKKK, SEQ ID NO: 62), MAP (KLALKLALKALKAALKLA, SEQ ID NO: 63), pVEC (LLIILRRRIRKQAHAHSK, SEQ ID NO: 64), Azurin-p28 (LSTAADMQGW TDGMASGLDKDYLKPDD, SEQ ID NO: 65), ARF (1-22) (MVRRFLVTLRIRRACGPPRVRV, SEQ ID NO: 66), DPV3 (RKKRRRESRKKRRRES, SEQ ID NO: 67), Antennapedia (RQIKIWFQNRRMKWKK , SEQ ID NO: 68), Antennapedia-Control (RQIKIWFQNRRMKWKKSTLWDTAELWQ, SEQ ID NO: 69), Antennapedia-NBD (RQIKIWFQNRRMKWKKTALDWSWLQTE, SEQ ID NO: 70), Antp-PKI (RQIKIWFQNRRMKWKKTYADFIASGRTGRRNAI, SEQ ID NO: 71), R8 (RRRRRRRR, SEQ ID NO: 72), Polyarginines ((R)n, n=6-12, SEQ ID NO: 73), Polyarginine-Control (RRRRRRRRRRRSTLWDTAELWQ, SEQ ID NO: 74), Polyarginine-NBD (RRRRRRRRRRRTALDWSWLQTE, SEQ ID NO: 75), Polyarginine-PKI (RRRRRRRRRRRTYADFIASGRTGRRNAI, SEQ ID NO: 76), R6W3 (RRWWRRWRR, SEQ ID NO: 77), ARF (19-31) (RVRVFW HIPRLT, SEQ ID NO: 78), Bip4 (VSALK, SEQ ID NO: 79), and LLLLRRRRRRRR (SEQ ID NO: 80).

[0041] Receptor Binding Peptides

[0042] The receptor binding peptide may be any peptide known to bind to a given receptor. In some embodiments, the receptor binding peptide is an angiotensin converting enzyme 2 receptor-binding protein (ACE2 RBP). In some embodiments, the receptor binding peptides comprise or consist of D-amino acids. In some embodiments, the receptor binding peptide is the retro-inverso version of the peptide known to bind the given receptor.

[0043] ACE2 RBPs may be any protein or peptide known in the art as being capable of binding angiotensin-converting enzyme 2 (ACE2). See e.g, US 9511120, and Huang L, et al. J Biol Chem. 2003; 278(18): 15532-15540, which are herein incorporated by reference in their entirety. While the ACE2 RBPs may inhibit ACE2, the ACE2 RBPs need not inhibit ACE2. Instead, the ACE2 RBPs need only bind ACE2. In some embodiments, the ACE2 RBPs comprise or consist of D-amino acids. In some embodiments, the ACE2 RBPs are the retro-inverso versions of peptides known to bind ACE2.

[0044] Exemplary ACE2 RBPs include DX500 (GSNRECHALFCMDFAPGEGGG SEQ ID NO: 81),

DX501 (GSSPTCRALFCVDFAPGEGGG SEQ ID NO: 82),

DX502 (GSLEMCEALFCVEFAPGEGGG SEQ ID NO: 83),

DX507 (GSNDYCTVFTGALFCLDFAPEGGG SEQ ID NO: 84),

DX514 (GSPNQCGVDIWALFCVDFAPEGGGK SEQ ID NO: 85),

DX504 (AGEGNCFLIGPWCFEFGTEGGG SEQ ID NO: 86),

DX508 (GSYDNCLGLANLNFCFDFAPEGGG SEQ ID NO: 87),

DX510 (GDDDDCGWIGFANFHLCLHGDPEGGG SEQ ID NO: 88),

DX511 (GDPFECDWGPWTLEMLCGPPDPEGGG SEQ ID NO: 89),

DX524 (GSRIGCRDSRCNWWAPGEGGG SEQ ID NO: 90),

DX525 (GSRGFCRDSSCSFPAPGEGGG SEQ ID NO: 91),

DX526 (GSWPTCLTMDCVYNAPGEGGG SEQ ID NO: 92),

DX527 (AGWVLCFEWEDCDEKGTEGGG SEQ ID NO: 93),

DX528 (AGVYFCFDWEQDCDEMGTEGGG SEQ ID NO: 94),

DX529 (AGWEVCHWAPMMCKHGGTEGGG SEQ ID NO: 95),

DX530 (AGQKECKFGYPHCLPWGTEGGG SEQ ID NO: 96),

DX531 (AGSDWCGTWNNPCFHQGTEGGG SEQ ID NO: 97),

DX512 (GDRLHCKPQRQSPWMKCQHLDPEGGG SEQ ID NO: 98),

DX513 (GDLHACRPVRGDPWWACTLGDPEGGG SEQ ID NO: 99),

DX599 (GDRYLCLPQRDKPWKFCNWFDPEGGG SEQ ID NO: 100),

DX600 (GDYSHCSPLRYYPWWKCTYPDPEGGG SEQ ID NO: 101),

DX601 (GDGFTCSPIRMFPWFRCDLGDPEGGG SEQ ID NO: 102), and DX602 (GDFSPCKALRHSPWWVCPSGDPEGGG SEQ ID NO: 103).

[0045] In some embodiments, the ACE2 RBP sequence comprises CX1PX2RX3X4PW5X6X7C (SEQ ID NO: 104), wherein XI to X7 are each independently any amino acid, preferably XI is K, R, L, or S; X2 is Q, V, L, or I; X4 is Q, G, D, Y, M, or H; X5 is S, D, K, Y, or F; X6 is M, W, K, or F; and X7 is K, A, F, R, or V. In some embodiments, the ACE2 RBP is DX512 (SEQ ID NO: 98) or DX600 (SEQ ID NO: 101).

[0046] (2B) ANTI-RNA AGENTS

[0047] The anti-RNA agent may be (i) a ribonuclease (RNase), preferably a member of the RNase H family of proteins, or (iii) an arogonaute protein, such as Argonaute 2. It is believed that inclusion of an anti-RNA agent in the modular therapeutics described herein will provide a more robust inactivation, e.g., degradation of the given target gene as compared to prior art therapeutics that rely upon a subject’s own enzymes that are endogenously produced in response to DNA:RNA and RNA:RNA complexes.

[0048] In some embodiments, where the therapeutic oligonucleotide and the target gene hybridize to form a DNA:RNA complex, the anti-RNA agent is preferably an RNase, more preferably a member of the RNase H family of proteins. In some embodiments, where the therapeutic oligonucleotide and the target gene hybridize to form a RNA:RNA complex, the anti-RNA agent is preferably an arogonaute protein, such as Argonaute 2.

[0049] Ribonucleases

[0050] The ribonuclease (RNase) may be any endoribonuclease or exoribonuclease in the art and derivatives thereof. Exemplary endoribonucleases include RNase A, RNase H, RNase III, RNase L, RNase P, RNase PhyM, RNaseTl, RNase T2, RNase U2, RNase V, RNase E, and RNase G. Exemplary exoribonucleases include PNPase, RNase PH, RNase R, RNase D, RNase T, Oligoribonuclease, Exoribonuclease I, and Exoribonuclease II. In some embodiments, the RNase is an endoribonuclease. In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to RNase H, partial (HIV 1) (Accession No. ABU62701.1, SEQ ID NO: 105). In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to A. coli RNase HI (Accession No. WP 000917883.1, SEQ ID NO: 106). In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to HIV-1 RNase H pi 5 with engineered E. coli loop and active site inhibitor (HIV-1) (Accession No. 3HYF A, SEQ ID NO: 107). In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to HIV-1 RNase HI (Accession No. ABE05737.1, SEQ ID NO: 108). In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to

X8X9QVEIFTDGSCLGNPGPGGYGAILRYRGREKTFSAGYTRTTNNRMELMAAIVAL EA LKEHCEVILSTDSQYVLQGITQWIHNWKKRGWKTADKKPVKNVDLWQRLDAALGQHQIK WEWYKGHAGHPENERCDELARAAAMNPTLEDTGYQVEV (SEQ ID NO: 109), wherein X8 and/or X9 may be present or absent and, if X8 is present, X8 is any amino acid, preferably M or L, and if X9 is present, X9 is any amino acid, preferably Y or K.

In some embodiments, the RNase has a sequence that is 90%, 91%, 92%, 93%, 94%,

95%, 96%, 97%, 98%, 99%, or 100% sequence identity to

X10MYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTNRGRQKW TLTDTTNQKTELQA IYLALQDSGLEVNIVTDSQYALQGITQWIHNWKKRGWKTADKKPX1 1KNVDLVNQIIEQ LIKKEKVYLAWVPAHKGIGGNEQVDKLVSAGIRKVL (SEQ ID NO: 110), wherein X10 and/or XI 1 may be present or absent and, if X10 is present, X10 may be any amino acid, preferably M, and if XI 1 is present, XI 1 may be any amino acid, preferably V.

[0051] Arogonaute Proteins

[0052] The arogonaute protein may be any protein comprising or consisting of a sequence that has 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to Argonaute 2 (Accession No. NP_036286.2, SEQ ID NO: 111).

[0053] FUSIONS

[0054] One or more components of the modular therapeutics, i.e., one or more therapeutic oligonucleotides, one or more targeting agents, and/or one or more anti-RNA agents may be fused together, i.e., linked directly (e.g, via a covalent bond) or indirectly (e.g, via a linker). The components of the fusions may be provided in any order. For example, in a fusion comprising a targeting agent and an anti-RNA agent, the anti-RNA agent may be upstream or downstream of the targeting agent. Using a fusion comprising two targeting agents, e.g, a CPP and an ACE2 RBP, and an anti-RNA agent, the anti- RNA agent may be upstream or downstream of both the targeting agents or the anti-RNA agent may be located between the targeting agents. In some embodiments, the one or more therapeutic oligonucleotides are fused to a targeting agent and/or an anti-RNA agent.

[0055] Fused components may be directly attached together via a covalent bond or via a linker. In embodiments where the components that are fused together are proteins, the linker is a protein linker, which may be flexible, rigid, or cleavable. See, e.g, Chen X, et al. Adv Drug Deliv Rev. 2013; 65(10): 1357-1369, which is herein incorporated by reference in its entirety. In some embodiments, the protein linker is a flexible linker such as Glycine-Serine linkers known in the art. See, e.g., Van Rosmalen M, et al. Biochemistry . 2017; 56(50): 6565-6574, which is herein incorporated by reference in its entirety. Oligonucleotides may be covalently attached to proteins using methods and/or linkers known in the art. See, for example, those described in Winkler, J. Ther Deliv. 2013, 4(7):791-809, Avino, et al. Chemistry Open. 2019, 8(3):382-387, Jablonski, et al. Nucleic Acid Res., 1986, 14, 6115-6128, Kahl & Greenberg J. Org. Chem., 1999, 64 (2), 507-510, Kachalova, et al. Nucleic Acids. 2000, 19, 1693-1707, Prakash, et al. Org.

Lett. 2003, 5, 403-406, Podyminogin, et al. Nucleic Acid Res., 2001, 29, 5090-5098, Raddatz, etal. Nucleic Acid Res., 2002, 30, 4793-4802, Timofeev, etal. Nucleic Acid Res., 1996, 24, 3142-3148, Rostovtsev, etal. Chem. Int. Ed., 2002, 41, 2596-2599, Ustinov, et al, Tetrahedron, 2007, 64, 1467-1473, Ming, et al. Nucleic Acid Symposium Series No. 52, 471-472, 2008, El-Saghner & Brown, Accounts of Chemical Research, 2012, 45(8), 1258-67, Debets, et al, Chem. Commun., 2010, 46, 97-99, Marcha, etal, Nucleic Acid Res., 2006, 34, e24, and US 20080050731, which are herein incorporated by reference in their entirety.

[0056] In some embodiments, the components of the modular therapeutics are substantially purified. As used herein, a “substantially purified” compound refers to a compound that is removed from its natural environment and/or is at least about 60% free, preferably about 75% free, and more preferably about 90% free, and most preferably about 95-100% free from other macromolecular components or compounds with which the compound is associated with in nature or from its synthesis.

[0057] In some embodiments, the components of the modular therapeutic are co administered. As used herein, “co-administered” refers to the administration of at least two different agents, i.e., a first agent (e.g, therapeutic oligonucleotide) and a second agent (e.g, a targeting agent-anti -RNA agent fusion such as a CPP-RNase fusion or a ACE2 RBP-CPP-RNase fusion) to a subject. In some embodiments, the co administration is concurrent. In embodiments involving concurrent co-administration, the agents may be administered as a single composition, e.g, an admixture, or as two separate compositions. In some embodiments, the first agent is administered before and/or after the administration of the second agent. Where the co-administration is sequential, the administration of the first and second agents may be separated by a period of time, e.g, minutes, hours, or days. Those of skill in the art understand that the formulations and/or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some embodiments, when two or more agents are co-administered, the respective agents are administered at lower dosages than appropriate for their administration alone.

[0058] Kits

[0059] In some embodiments, the present invention provides kits comprising one or more modular therapeutics, optionally in a composition, packaged together with one or more reagents or drug delivery devices for preventing, inhibiting, reducing, or treating COVID disease in a subject. In some embodiments, the kits comprise the one or more modular therapeutics, optionally in one or more unit dosage forms, packaged together as a pack and/or in drug delivery device, e.g ., a pre-filled syringe.

[0060] In some embodiments, the kits include a carrier, package, or container that may be compartmentalized to receive one or more containers, such as vials, tubes, and the like. In some embodiments, the kits optionally include an identifying description or label or instructions relating to its use. In some embodiments, the kits include information prescribed by a governmental agency that regulates the manufacture, use, or sale of compounds and compositions as contemplated herein.

[0061] Compositions

[0062] Compositions, including pharmaceutical compositions, comprising one or more modular therapeutics are contemplated herein. The term “pharmaceutical composition” refers to a composition suitable for pharmaceutical use in a subject. A composition generally comprises an effective amount of an active agent and a diluent and/or carrier.

A pharmaceutical composition generally comprises a therapeutically effective amount of an active agent and a pharmaceutically acceptable carrier.

[0063] As used herein, an “effective amount” refers to a dosage or amount sufficient to produce a desired result. The desired result may comprise an objective or subjective change as compared to a control in, for example, in vitro assays, and other laboratory experiments. As used herein, a “therapeutically effective amount” refers to an amount that may be used to treat, prevent, or inhibit a given disease or condition in a subject as compared to a control, such as a placebo. Again, the skilled artisan will appreciate that certain factors may influence the amount required to effectively treat a subject, including the degree of the condition or symptom to be treated, previous treatments, the general health and age of the subject, and the like. Nevertheless, effective amounts and therapeutically effective amounts may be readily determined by methods in the art.

[0064] The one or more modular therapeutics may be administered, preferably in the form of pharmaceutical compositions, to a subject. Preferably the subject is mammalian, more preferably, the subject is human. Preferred pharmaceutical compositions are those comprising at least one modular therapeutic in a therapeutically effective amount and a pharmaceutically acceptable vehicle. In some embodiments, a therapeutically effective amount of a modular therapeutic ranges from about 0.0 - 10 mg/kg body weight, about 0.01 - 3 mg/kg body weight, about 0.01 - 2 mg/kg, about 0.01 - 1 mg/kg, or about 0.01 - 0.5 mg/kg body weight for parenteral formulations. Therapeutically effective amounts for oral administration may be up to about 10-fold higher. It should be noted that treatment of a subject with a therapeutically effective amount may be administered as a single dose or as a series of several doses. The dosages used for treatment may increase or decrease over the course of a given treatment. Optimal dosages for a given set of conditions may be ascertained by those skilled in the art using dosage-determination tests and/or diagnostic assays in the art. Dosage-determination tests and/or diagnostic assays may be used to monitor and adjust dosages during the course of treatment.

Pharmaceutical compositions may be formulated for the intended route of delivery and administered to subjects accordingly using methods in the art. Suitable routes of delivery include auricular, buccal, conjunctival, cutaneous, dental, electro osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra-amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavernous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, intracoronary, intracorporus cavernosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory, retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and/or vaginal delivery routes. It will be appreciated that the preferred route of administration and pharmaceutical formulation will vary with the condition and age of the subject, the nature of the condition to be treated, the therapeutic effect desired, and the particular modular therapeutic used.

[0065] Pharmaceutical compositions may include one or more of the following: a pharmaceutically acceptable vehicle, pH buffered solutions, adjuvants ( e.g ., preservatives, wetting agents, emulsifying agents, and dispersing agents), liposomal formulations, nanoparticles, dispersions, suspensions, or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions. The compositions and formulations may be optimized for increased stability and efficacy using methods in the art. See, e.g., Carra et al., (2007) Vaccine 25:4149-4158.

[0066] As used herein, a “pharmaceutically acceptable vehicle” or “pharmaceutically acceptable carrier” are used interchangeably and refer to solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration and comply with the applicable standards and regulations, e.g. , the pharmacopeial standards set forth in the United States Pharmacopeia and the National Formulary (USP-NF) book, for pharmaceutical administration. Thus, for example, unsterile water is excluded as a pharmaceutically acceptable carrier for, at least, intravenous administration. Pharmaceutically acceptable vehicles include those known in the art. See, e.g, Remington: The Science and Practice of Pharmacy 20th ed (2000) Lippincott Williams & Wilkins, Baltimore, MD.

[0067] The term “pharmaceutically acceptable salts” refers to salt forms that are pharmacologically acceptable and substantially non-toxic to the subject being treated with the compound of the invention. Pharmaceutically acceptable salts include conventional acid-addition salts or base-addition salts formed from suitable non-toxic organic or inorganic acids or inorganic bases. Exemplary acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, methanesulfonic acid, ethane- disulfonic acid, isethionic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, 2-acetoxybenzoic acid, acetic acid, phenylacetic acid, propionic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid, glutamic acid, salicylic acid, sulfanilic acid, and fumaric acid. Exemplary base-addition salts include those derived from ammonium hydroxides ( e.g ., a quaternary ammonium hydroxide such as tetramethylammonium hydroxide), those derived from inorganic bases such as alkali or alkaline earth-metal (e.g., sodium, potassium, lithium, calcium, or magnesium) hydroxides, and those derived from non-toxic organic bases such as basic amino acids.

[0068] A “pharmaceutically acceptable prodrug” is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or to a pharmaceutically acceptable salt of such compound. A “pharmaceutically active metabolite” refers to a pharmacologically active product produced through metabolism in the body of a specified compound or salt thereof. Prodrugs and active metabolites of a compound may be identified using routine techniques known in the art. See, e.g, Bertolini, G. et al., (1997) J. Med. Chem. 40:2011-2016; Shan, D. et al., J. Pharm. Sci., 86(7):765-767; Bagshawe K., (1995) Drug Dev. Res. 34:220-230; Bodor, N., (1984) Advances in Drug Res. 13:224-331; Bundgaard, EL, Design of Prodrugs (Elsevier Press, 1985) and Larsen, I. K., Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen etal., eds., Harwood Academic Publishers, 1991).

[0069] The pharmaceutical compositions may be provided in dosage unit forms. As used herein, a “dosage unit form” refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of the one or more modular therapeutic calculated to produce the desired therapeutic effect in association with the required pharmaceutically acceptable carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the given modular therapeutic and desired therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

[0070] Toxicity and therapeutic efficacy of modular therapeutics according to the instant invention and compositions thereof can be determined using cell cultures and/or experimental animals and pharmaceutical procedures in the art. For example, one may determine the lethal dose, LCso (the dose expressed as concentration x exposure time that is lethal to 50% of the population) or the LDso (the dose lethal to 50% of the population), and the EDso (the dose therapeutically effective in 50% of the population) by methods in the art. The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50. modular therapeutics which exhibit large therapeutic indices are preferred. While modular therapeutics that result in toxic side- effects may be used, care should be taken to design a delivery system that targets such compounds to the site of treatment to minimize potential damage to uninfected cells and, thereby, reduce side-effects.

[0071] The data obtained from the cell culture assays and animal studies can be used in formulating a range of dosages for use in humans. Preferred dosages provide a range of circulating concentrations that include the ED50 with little or no toxicity. The dosage may vary depending upon the dosage form employed and the route of administration utilized. Therapeutically effective amounts and dosages of one or more modular therapeutics can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (i.e., the concentration of the test compound which achieves a half- maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Levels in plasma may be measured, for example, by high performance liquid chromatography. Additionally, a dosage suitable for a given subject can be determined by an attending physician or qualified medical practitioner, based on various clinical factors.

[0072] The following examples are intended to illustrate but not to limit the invention.

[0073] EXAMPLES

[0074] Exemplified herein are modular therapeutics for treating or inhibiting a COVID disease, such as COVID- 19.

[0075] MATERIALS

[0076] FANA oligonucleotides (AUM Lifetech PA, Philadelphia, PA). HIV Reverse

Transcriptase Recombinant (#382129-500U, Millipore Sigma, Billerica, MA). Ribonuclease H, E. coli (#M0297S, NEB, Beverly, MA). RNA oligo 5'- GAUCUGAGCCUGGGAGCU-3 ' (SEQ ID NO: 112) having a fluorescent label, i.e., 6-carboxyfluorescein attached to its 3’ end. DNA oligo (5'-

AGCTCCCAGGCTCAGATC-3 ' (SEQ ID NO: 113) having Dabcyl attached to its 5’ end. [0077] TARGETING AGENT - ANTI-RNA AGENT FUSIONS

[0078] Two exemplary targeting agent-anti-RNA agent fusions, (1) a CPP-RNase fusion, and (2) an ACE2 RBP-CPP-RNase fusion, were made using methods in the art.

[0079] (1) a CPP-RNase fusion

[0080] The amino acid sequence of the construct for the CPP-RNase fusion is as follows:

[ LDMEDNDI IEAHREQIG] ( LLLLRRRRRRRRR ) GGGGSMYQLEKEPIVGAETFYVDGA ANRETKLGKAGYVTNRGRQKVVTLTDTTNQKTELQAIYLALQDSGLEVNIVTDSQYALQ GITQWIHNWKKRGWKTADKKPVKNVDLVNQIIEQLIKKEKVYLAWVPAHKGIGGNEQVD KLVSAGIRKVL ( SEQ ID NO : 114 ) , wherein the SUMO sequence is in brackets, the CPP sequence is in parenthetical s, the linker is underlined, and the anti-RNA agent is italicized.

[0081] The nucleic acid sequence of the construct for the CPP-RNase fusion is as follows:

C C T GAG G [ AT C T G GAC AT G GAAGACAAT GAC AT T AT C GAAG C T C AT C G T GAAC AGAT T G GTGGT ] ( CTGCTGCTGCTGCGTCGCCGTCGCCGTCGCCGCCGTCGC ) GGCGGTGGCGGT AGGATGTACCAGCTGGAGAAAGAACCGATCGTGGGCGCGGAAACCTTCTACGTTGATGG CGCCGCCAACCGCGAAACCAAACTGGGCAAAGCCGGCTACGTTACGAACCGCGGTCGCC AGAAGGTTGTGACGCTGACGGATACCACGAACCAGAAAACCGAACTGCAAGCCATCTAT CTGGCGCTGCAAGATAGCGGTCTGGAAGTGAACATCGTGACCGATAGCCAGTACGCGCT GCAAGGCATCACGCAGTGGATTCACAACTGGAAGAAACGCGGCTGGAAGACCGCGGACA AAAAACCGG TGAAGAACG TGGA TC TGG TGAA TCAGA TCA TCGAGCAGCTGA TCAAGAAG GAGAAGGTGTATCTGGCGTGGGTGCCGGCGCATAAAGGTATTGGCGGCAACGAACAAGT TGACAAACTGGTGAGCGCGGGTATTCGCAAAGTTCTGYAA ( SEQ ID NO : 115 ) , wherein the SUMO sequence is in brackets, the CPP sequence is in parenthetical s, the linker is underlined, and the anti-RNA agent is italicized.

[0082] The resulting sequence of the CPP-RNase fusion after removal of the SUMO sequence is as follows:

( LLLLRRRRRRRRR) GGGGSMYQLEKEPIVGAETFYVDGAANRETKLGKAGYVTNRGRQ KVVTLTDTTNQKTELQAIYLALQDSGLEVNIVTDSQYALQGITQWIHNWKKRGWKTADK KPVKNVDL VNQIIEQL IKKEKVYLAWVPAHKGIGGNEQVDKL VSAGIRKVL ( SEQ ID NO : 116 ) , wherein the CPP sequence is in parentheticals (SEQ ID NO: 80), the linker is underlined, and the anti-RNA agent is italicized (SEQ ID NO: 110, wherein X10 is absent and XI 1 is V).

[0083] (2) ACE2 RBP-CPP-RNase fusion

[0084] The amino acid sequence of the construct for the ACE2 RBP-CPP-RNase fusion is as follows: [ LDMEDNDI IEAHREQIGG ] GDYSHCSPLRYYPWWKCTYPDPGGGGSGGGGSGGGGS ( L

LLLRRRRRRRRR ) AEAAAKEAAAKAMYQLEKEPIVGAE TFYVDGAANRE TKL GKAGYVT NRGRQKVVTLTDTTNQKTELQAIYLALQDSGLEVNIVTDSQYALQGITQWIHNWKKRGW K TADKKPVKNVDL VNQIIEQL IKKEKVYLAWVPAHKGIGGNE QVDKLVSAGIRKVL ( SEQ ID NO : 117 ) , wherein the SUMO sequence is in brackets, the CPP sequence is in parenthetical s, the linker is underlined, the anti-RNA agent is italicized, and the ACE2 RBP sequence is double underlined.

[0085] The nucleic acid sequence of the construct for the ACE2 RBP-CPP-RNase fusion is as follows:

C C T GAG G [ AT C T G GAC AT G GAAGACAAT GAC AT T AT C GAAG C T C AT C G T GAAC AGAT T G GTGGT ] GGCGATTATAGCCATTGCAGCCCGCTGCGCTATTATCCGTGGTGGAAATGCAC CTATCCGGATCCGGGCGGTGGCGGCGGTGGCGGCGGCAGCGGTGGCGGCGGCAGC ( CTG CTGCTGCTGCGTCGCCGTCGCCGTCGCCGCCGTCGC ) GCGGAAGCCGCGGCCAAAGAAG CGGCCGCGAAAGCGATGTACCAGCTGGAGAAAGAACCGATCGTGGGCGCGGAAACCTTC TACGTTGATGGCGCCGCCAACCGCGAAACCAAACTGGGCAAAGCCGGCTACGTTACGAA CCGCGGTCGCCAGAAGGTTGTGACGCTGACGGATACCACGAACCAGAAAACCGAACTGC AAGCCATCTATCTGGCGCTGCAAGATAGCGGTCTGGAAGTGAACATCGTGACCGATAGC CAGTACGCGCTGCAAGGCATCACGCAGTGGATCCACAACTGGAAGAAACGCGGCTGGAA GACCGCGGACAAAAAACCGG TGAAGAACG TGGA TC TGG TGAA TCAGA TCA TCGAGCAGC TGATCAAGAAGGAGAAGGTGTATCTGGCGTGGGTGCCGGCGCATAAAGGTATTGGCGGC AACGAACAAGTTGACAAACTGGTGAGCGCGGGTATTCGCAAAGTTCTGTAAGTGGAG ( SEQ ID NO : 118 ) , wherein the SUMO sequence is in brackets, the CPP sequence is in parenthetical s, the linker is underlined, the anti-RNA agent is italicized, and the ACE2 RBP sequence is double underlined.

[0086] The resulting sequence of the ACE2 RBP-CPP-RNase fusion after removal of the SUMO sequence is as follows:

GDYSHCSPLRYYPWWKCTYPDPEGGGGSGGGGSGGGGS ( LLLLRRRRRRRRR ) AEAAAK EAAAKAMY QLEKEPIVGAE TF YVDGAANRE TKL GKAGYVTNRGRQKVVTL TD T TNQK TE LQAIYLALQDSGLEVNIVTDSQYALQGITQWIHNWKKRGWKTADKKPVKNVDLVNQIIE QLIKKEKVYLAWVPAHKGIGGNEQVDKLVSAGIRKVL ( SEQ ID NO : 119 ) , wherein the CPP sequence is in parentheticals(SEQ ID NO: 80), the linker is underlined, the anti-RNA agent is italicized (SEQ ID NO: 110, wherein XI 0 is absent and XI 1 is V), and the ACE2 RBP sequence is double underlined (SEQ ID NO: 101).

[0087] The targeting agent-anti-RNA agent fusions were synthesized using an E. coli expression system. Constructs of the targeting agent-anti-RNA agent fusions were synthesized with a multi-histidine amino acid tag and a SUMO at the N-terminus end, which is removed after purification. Specifically, the above nucleic acid sequences of the fusions above were each chemically synthesized. The resulting constructs were then cloned into plasmid vectors using the Bsu36I and Xhol restriction enzyme sites of the Trialtus vector 21. The nucleotide sequence for both constructs were optimized for expression in E. coli. BL-2 (DE3) E. coli cells were transformed with the nucleic acid constructs. Bacterial cell colonies expression the fusions were positively selected.

[0088] A single E. coli colony, verified for expected protein expression, was inoculated into 250 mL of LB-medium in a 1 L flask. A pre-culture was grown overnight at 37°C and 220 rpm and was used to inoculate 6 L of LB-Kanamycin medium (6X 1 L media in 4 L flasks). The final culture was grown at 37°C until the OD600 = 0.6, then rapidly cooled to about 20°C. The expression was induced at OD600 = 0.7 by adding Isopropyl_P-D- l -thiogalactopyranoside (IPTG) at a final concentration of 200 mM.

After the IPTG induction, cells were grown for 16 hours at 22°C and 250 rpm to the final OD600 of 1.85 for the CPP-RNase fusion and 2.05 for the ACE2 RBP-CPP-RNase fusion. Cells were collected by centrifugation (4,000 x g for 25 minutes) and resuspended in 250 mL of Buffer A (20 mM Tris/HCl pH 8.0, 5% glycerol) containing 0.5 M NaCl and supplemented with the protease inhibitor cocktail (#P8849, Sigma, Billerica, MA). To ensure protein solubility the concentration of NaCl was kept at a minimum level of 400 mM all throughout purification process.

[0089] Harvested E. coli cells were lysed by sonication. To remove cellular debris, the lysate was subjected to ultracentrifugation at 250,000xg for 45 minutes. The supernatant was loaded onto cobalt HisTALON affinity column (#635683, Takara Bio) previously equilibrated with the Buffer A with 0.5 M NaCl. The column was thoroughly washed by a triple wash of 10 column volumes (each) with Buffer A containing consequently 0.5, 1.5 and 0.5 M NaCl.

[0090] The ACE2 RBP-CPP-RNase fusion was subjected to the following additional protocol to result in a disulfide bond between the cysteine residues in the ACE2 RBP sequence, the fusion protein was slowly oxidized by a combination of reduced glutathione (GSH) and oxidized (GSSG) in a form of a shallow linear gradient (40 column volumes at a flow rate of 0.15 mL/min) from 5 mM GSH to 5 mM GSSG, followed by another wash cycle.

[0091] Each fusion was then eluted in 10 column volumes of Buffer A with 0.5 M NaCl and 250 mM imidazole, collecting fractions of 2 mL each. Fractions were analyzed by SDS-PAGE; those containing the fusion product were combined, concentrated, and dialyzed against Buffer B (20 mM HEPES pH 7.6, 400 mM NaCl). For the tag removal, SUMO protease (#3333, Trialtus, Birmingham, AL) was added at the amount of 2% of the total protein. The cleavage was performed at 44°C for 48 hours (due to the high salt content). The digested fusions were further purified by Source 15S anion-exchange column (#17094410, Cytiva), applying 20 column volumes linear gradient of 0.4-1.2M NaCl. At the final purification step the fusions were passed through HisTrap HP column (#29051021, Cytiva, Marlborough, MA) to remove the undigested portion. The fusions were eluted from the column with 50 mM imidazole and dialyzed against Buffer B. For making the final preparation the concentration of NaCl was reduced to 200 mM by slow dilution with 20 mM HEPES pH 7.6. MnCh was additionally added to a final concentration of 5 mM.

[0092] Protein concentrations were measured using the NanoDrop ND-1000 spectrophotometer. Purity levels were estimated via SDS-PAGE analysis. After purification, 73.5 mg of the CPP-RNase fusion and 25.5 mg of the ACE2 RBP-CPP- RNase fusion were obtained. Purity of the fusions was demonstrated by one substantial protein remaining after purification, as viewed on a standard SDS detergent polyacrylamide gel after electrophoresis and staining of proteins by Coomassie blue dye.

[0093] RNASE ACTIVITY ASSAYS

Assays known in the art, e.g ., fluorescence molecular beacon assays, known in may be used to assay the nucleic acid digestion-degradation activity of the therapeutic oligonucleotide: target gene complex.

[0094] Assays were carried out at room temperature in a total volume of 40 pL in assay buffer consisting of 50 mM Tris-HCl pH 8.0, 60 mM KC1, and either 5 mM MgCk, or 5.6 mM MnCh. In each assay well of a black 384-well plate, 20 pL of a 2X solution of the indicated enzyme construct, diluted in assay buffer, was mixed with 20 pL of 500 nM RNA/DNA duplex (representing a therapeutic oligonucleotide: target gene complex) also in assay buffer. The increase in fluorescence upon cleavage of the RNA/DNA duplex was measured over time on a PerkinElmer Envision plate reader using a 485 nm excitation filter and a 535 nm emission filter.

[0095] HIV Reverse Transcriptase Recombinant (HIV-RT) is a large protein that has a small domain that confers its RNAse H activity (e.g., residues from about 592 to about 715 of Accession No. AAA83392.1). Thus, the activities of comparable moles per liter of HIV-RT, ACE2 RBP-CPP-RNase fusion, and CPP-RNase fusion, i.e., 2.7 nM of HIV- RT, 12.5 nM of CPP-RNase fusion (SEQ ID NO: 116), and 6.25 nM of ACE2 RBP- CPP-RNase fusion (SEQ ID NO: 119). It should be noted that E. coli RNase H exhibits activity only in the presence of manganese (Mn). Because the RNase domain (i.e., SEQ ID NO: 110, wherein X10 is absent and XI 1 is V) that was employed as the anti-RNA agent in the fusion proteins is in part derived from E. coli RNase H, the lack of activity with the buffer having MgCb (and not MnCb) was not surprising.

[0096] RNase activity was determined for the fusions and both demonstrated robust

RNase activity. RNase H activities of the fusions were compared to that of both the commercially available HIV RT protein (that contains RNase H activity) and E. coli RNase H. The ACE2 RBP-CPP-RNase fusion (in the presence of Mg) exhibited higher levels RNase H activity compared to the CPP -RNase fusion and the commercially available HIV RT protein. See Figure 1. Thus, these RNase activity assays indicate that exogenously administered anti-RNA agents fused to one or more targeting agents, will exhibit nucleic acid digestion-degradation activity against a given target gene of interest when the therapeutic oligonucleotide is annealed thereto. As such, it is expected that the modular therapeutics described herein will exhibit significantly more nucleic acid digestion-degradation activity of a therapeutic oligonucleotide: target gene complex compared to reliance upon proteins and mechanisms that are endogenous to the subject being treated, i.e., administration of a therapeutic oligonucleotide alone or in combination with a targeting agent and in the absence of an exogenously administered anti-RNA agent.

[0097] It is also believed that modular therapeutics having the given therapeutic oligonucleotide covalently attached to the one or more anti-RNA agents (which may be fused to the one or more targeting agents) will exhibit higher levels of acid digestion- degradation activity against a given target gene of interest when the therapeutic oligonucleotide is annealed thereto compared to mixtures of therapeutic oligonucleotides and anti-RNA agents (which may be fused to a targeting agent), i.e., “free” therapeutic oligonucleotides that are not covalently attached to the exogenously administered anti- RNA agents.

[0098] IN VITRO ANTI-SARS-CoV-2 ACTIVITY ASSAYS

[0099] The following modular therapeutic compositions were assayed for activity against SARS-CoV-2:

• therapeutic oligonucleotide + SEQ ID NO: 98 or SEQ ID NO: 101 as the ACE2 Receptor-Binding Peptide (ACE2 RBP)

• therapeutic oligonucleotide + CPP -RNase fusion (SEQ ID NO: 116)

• therapeutic oligonucleotide + ACE2 RBP-CPP-RNase fusion (SEQ ID NO: 119) and the therapeutic oligonucleotide was a given coronavirus oligonucleotide. The given coronavirus oligonucleotide and the given protein portion are provided in a 1:1 molar ratio in each modular therapeutic composition.

[0100] Briefly, the modular therapeutic compositions were titrated in DMSO and dispensed into 384-well assay plates at 60 nL/well. Cell culture media (MEM comprising 1% Pen/Strep/GlutaMax, 1% HEPES (buffer), and 2% HI FBS fetal bovine serum) was dispensed at 5 pL/well into assay plates and incubated at room temperature for about 30 minutes.

[0101] Vero E6 African green monkey kidney epithelial cells, about 4000 cells/well, were selected for high ACE2 expression and inoculated with SARS CoV-2 (Accession No. MN985325.1) at multiplicity of infection (MOI) of 0.002 (about 2 virus particles per 1000 cells) in cell culture liquid and dispensed into assay plates as 25 pL/well. The final cell density was 4000 cells/well. Assay plates were incubated for 72 hours at 37°C, 5% CO2, 90% humidity.

[0102] CellTiter-Glo (30 pL, #G7573 Promega, Madison, WI) was dispensed into each well and incubated for 10 minutes at room temperature. Cell lysis results in a luminescent signal that is proportional to the amount of ATP present. The amount of ATP is directly proportional to the number of cells present in culture. Dead cells have no ATP upon lysis, thereby resulting in no fluorescent signal. A fluorescent signal indicates that the modular therapeutic exhibits antiviral activity. Luminescence signal was measured on Perkin Elmer Envision or BMG CLARJOstar plate readers. An ATP content cytotoxicity counter-assay (control) was conducted using the same protocol but without the addition of SARS-CoV-2 virus.

[0103] IN VIVO ANTI-SARS-CoV-2 ACTIVITY ASSAYS

[0104] For in vivo animal studies, the Syrian hamster, Mesocricetus auratus, may be used. Hamsters infected with SARS-CoV-2 will lose weight, became lethargic, and develop ruffled fur and a hunched posture as well as rapid breathing. When hamsters are infected, high levels of SARS-CoV-2 are found in the hamsters’ lungs and intestines. To determine the efficacy of modular-component therapeutics to inhibit SARS-CoV-2 (COVID-19) infection in animals we will use a Syrian hamster model of SARS-CoV-2 infection using methods in the art. See , e.g. , Sia, etal. Pathogenesis and transmission of SARS-CoV-2 in golden hamsters. Nature. 2020;583(7818):834-838.

[0105] Briefly, 6-week-old male golden Syrian hamsters ( Mesocricetus auratus) are randomly segregated into groups. Each group of hamsters is inoculated intranasally or intrapulmonary with 4-40,000 PFU of SARS-CoV-2. After two days, post-infection (dpi.), lungs are harvested for qRT-PCR analysis to detect viral nucleic acids present in tissues. SARS-CoV-2 is inoculated into animals by intranasal delivery of 1,000 PFU (plaque forming units) per animal. Four hours after virus inoculation, the animals of each group are administered, preferably intranasally or intrapulmonary, a given modular therapeutic composition at 400 ng (about 2.5 pg/kg, low dose) or 1.2 pg (about 7.5 pg/kg, high dose). Control subjects are administered a placebo. At 2 days after infection, lung tissue is taken for further analysis. Viral titers may also be assayed. Two days after infection control subjects are expected to exhibit symptoms of COVID disease, e.g ., ruffled coat hair, hunched posture, and coughing, and treated subjects are expected to show little to no symptoms of COVID disease and lower viral titers if any as compared to untreated controls.

[0106] To show that the modular therapeutic compositions comprising coronavirus oligonucleotides may prophylactically prevent or inhibit COVID disease in subjects, a group of hamsters are administered the modular therapeutic compositions at least about 1 hour prior to challenge with SARS-CoV-2. It is expected that prophylactically treated subjects will exhibit little to no symptoms of COVID disease and lower viral titers if any as compared to untreated controls.

[0107] To show that the modular therapeutic compositions comprising coronavirus oligonucleotides may be used to treat advanced COVID disease in subjects, a group of hamsters will not be administered the modular therapeutic compositions at least 24 hours after challenge with SARS-CoV-2. It is expected that subjects in this group will exhibit reduced symptoms of COVID disease and lower viral titers as compared to untreated controls.

[0108] Similar experiments may be conducted in non-human primates such as the rhesus macaque.

[0109] Overall, it is expected that the modular therapeutics as disclosed herein, e.g. , (a) therapeutic oligonucleotide + CPP-RNase fusion (e.g. , SEQ ID NO: 116) and (b) therapeutic oligonucleotide + ACE2 RBP-CPP-RNase fusion (e.g, SEQ ID NO: 119), will exhibit significantly superior in vitro and in vivo activities compared compositions that lacking an anti-RNA agent, e.g, therapeutic oligonucleotide + ACE2 Receptor- Binding Peptide (ACE2 RBP).

[0110] All scientific and technical terms used in this application have meanings commonly used in the art unless otherwise specified. [0111] As used herein, the terms “subject”, “patient”, and “individual” are used interchangeably to refer to humans and non-human animals. The terms “non-human animal” and “animal” refer to all non-human vertebrates, e.g ., non-human mammals and non-mammals, such as non-human primates, horses, sheep, dogs, cows, pigs, chickens, and other veterinary subjects and test animals. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0112] As used herein, a “COVID disease” refers to a disease, such as COVID-19, caused by an infection by a coronavirus. As used herein, a “coronavirus” refers to any virus classified as belonging to Coronaviridae . In some embodiments, the coronavirus is an alphacoronavirus. In some embodiments, the coronavirus is a betacoronavirus. In some embodiments, the coronavirus is a gammacoronavirus. In some embodiments, the coronavirus is a deltacoronavirus. In some embodiments, the coronavirus is a Severe Acute Respiratory Syndrome-Related Coronavirus strain (e.g, SARS-CoV, SARS-CoV- 2). In some embodiments, the coronavirus is a Middle East Respiratory Syndrome- Related Coronavirus strain (e.g, MERS-CoV). In some embodiments, the coronavirus has a genome that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to Accession No. NC_004718.3 (SARS-CoV), Accession Nos. NC_045512.2 or MN985325.1 (SARS-CoV-2), or Accession No. NC_019843.3 (MERS- CoV).

[0113] As used herein, “coronavirus sequences” include nucleic acid sequences of a coronavirus and the complements, reverse sequences, and reverse complements thereof. Coronavirus sequences include those having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to Accession Nos. NC_004718.3, NC_045512.2, MN985325.1, NC_019843.3, and the complements, reverse sequences, and reverse complements thereof. In some embodiments, the coronavirus sequences encode the proteins (e.g, spike (S) proteins, nucleocapsid (N) proteins, matrix/membrane (M) proteins, envelope (E) proteins, RNA dependent RNA polymerases (RdRp)) of a coronavirus. In some embodiments, the coronavirus sequence encodes a protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to Accession No. MW301192.1 or the complement, reverse, or reverse complement of Accession No. MW301192.1. In some embodiments, the coronavirus sequence encodes a protein having 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to Accession No. QPI75814.1 or the complement, reverse, or reverse complement of Accession No. QPI75814.1. [0114] As used herein, the terms “protein”, “polypeptide” and “peptide” are used interchangeably to refer to two or more amino acids linked together. Groups or strings of amino acid abbreviations are used to represent peptides. Except when specifically indicated, peptides are indicated with the N-terminus on the left and the sequence is written from the N-terminus to the C-terminus. Except when specifically indicated, peptides are indicated with the N-terminus on the left and the sequences are written from the N-terminus to the C-terminus. Similarly, except when specifically indicated, nucleic acid sequences are indicated with the 5’ end on the left and the sequences are written from 5’ to 3’.

[0115] As used herein, the terms “polynucleotide”, “oligonucleotide”, and “nucleic acid molecule” are used to refer to two or more nucleotides linked together. The “nucleotides” may be naturally occurring or synthetic, e.g ., ribonucleotides, deoxyribonucleotides, 2'-deoxy-2'-fluoroarabino nucleic acids (FANAs), 2'-0-methyl oligoribonucleotides, 4'-C-aminoethyl-2'-fluoro analogs, and/or 4'-C-aminoethyl-2'-0- methyl analogs known in the art. See e.g., Majlessi M, et al. Nucleic Acids Res. 1998; 26(9): 2224-2229; Malek-Adamian E, etal. J Am Chem Soc. 2017; 139(41): 14542- 14555. FANAs increase resistance against nucleases and improve binding affinity. FANAs, particularly chimeric FANA-DNA allele-specific oligonucleotides (ASOs), elicit RNase H-mediated cleavage of target RNA. In some embodiments, the therapeutic oligonucleotides comprise or consist of synthetic nucleotides, preferably FANAs. In some embodiments, the therapeutic oligonucleotides comprise both naturally occurring nucleotides and synthetic nucleotides. In some embodiments, the therapeutic oligonucleotides comprise both deoxyribonucleotides and FANAs. In some embodiments, the therapeutic oligonucleotides comprise both ribonucleotides and FANAs. For purposes herein, FANAs are synthetic nucleic acids. In some embodiments, the complex formed by an oligonucleotide comprising or consisting of FANAs hybridized to a DNA molecule is categorized as being a DNA:RNA complex, and a complex formed by an oligonucleotide comprising or consisting of FANAs hybridized to an RNA molecule is categorized as being an RNA:RNA complex.

[0116] As used herein, a given percentage of “sequence identity” refers to the percentage of nucleotides or amino acid residues that are the same between sequences, when compared and optimally aligned for maximum correspondence over a given comparison window, as measured by visual inspection or by a sequence comparison algorithm in the art, such as the BLAST algorithm, which is described in Altschul et al, (1990) J Mol Biol 215:403-410. Software for performing BLAST ( e.g ., BLASTP and BLASTN) analyses is publicly available through the National Center for Biotechnology Information (ncbi.nlm.nih.gov). The comparison window can exist over a given portion, e.g., a functional domain, or an arbitrarily selection a given number of contiguous nucleotides or amino acid residues of one or both sequences. Alternatively, the comparison window can exist over the full length of the sequences being compared. For purposes herein, where a given comparison window (e.g, over 80% of the given sequence) is not provided, the recited sequence identity is over 100% of the given sequence.

Additionally, for the percentages of sequence identity of the proteins provided herein, the percentages are determined using BLASTP 2.8.0+, scoring matrix BLOSUM62, and the default parameters available at blast.ncbi.nlm.nih.gov/Blast.cgi. See also Altschul, el al., (1997) Nucleic Acids Res 25:3389-3402; and Altschul, etal, (2005) FEBS J 272:5101- 5109.

[0117] Optimal alignment of sequences for comparison can be conducted, e.g, by the local homology algorithm of Smith & Waterman, Adv Appl Math 2:482 (1981), by the homology alignment algorithm of Needleman & Wunsch, J Mol Biol 48:443 (1970), by the search for similarity method of Pearson & Lipman, PNAS USA 85:2444 (1988), by computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, WI), or by visual inspection.

[0118] Nucleic acid molecules and proteins may be made using methods known in the art including chemical synthesis, biosynthesis or in vitro synthesis using recombinant DNA methods, and solid phase synthesis. See, e.g, Kelly & Winkler (1990) Genetic Engineering Principles and Methods, vol. 12, J. K. Setlow ed., Plenum Press, NY, pp. 1- 19; Merrifield (1964) J Amer Chem Soc 85:2149; Houghten (1985) PNAS USA 82:5131-5135; and Stewart & Young (1984) Solid Phase Peptide Synthesis, 2ed. Pierce, Rockford, IL, which are herein incorporated by reference. Proteins may be purified using protein purification techniques known in the art such as reverse phase high- performance liquid chromatography (HPLC), ion-exchange or immunoaffmity chromatography, filtration or size exclusion, or electrophoresis. See, e.g, Olsnes and Pihl (1973) Biochem. 12(16):3121-3126; and Scopes (1982) Protein Purification, Springer-Verlag, NY, which are herein incorporated by reference.

[0119] As used herein, an “isolated” compound refers to a compound that is isolated from its native environment. For example, an isolated polynucleotide is a one which does not have the bases normally flanking the 5’ end and/or the 3’ end of the polynucleotide as it is found in nature. As another example, an isolated polypeptide is a one which does not have its native amino acids, which correspond to the full-length polypeptide, flanking the N-terminus, C-terminus, or both.

[0120] The use of the singular can include the plural unless specifically stated otherwise.

As used in the specification and the appended claims, the singular forms “a”, “an”, and “the” can include plural referents unless the context clearly dictates otherwise.

[0121] As used herein, “and/or” means “and” or “or”. For example, “A and/or B” means

“A, B, or both A and B” and “A, B, C, and/or D” means “A, B, C, D, or a combination thereof’ and said “A, B, C, D, or a combination thereof’ means any subset of A, B, C, and D, for example, a single member subset ( e.g ., A or B or C or D), a two-member subset (e.g., A and B; A and C; etc.), or a three-member subset (e.g, A, B, and C; or A, B, and D; etc.), or all four members (e.g, A, B, C, and D).

[0122] As used herein, the phrase “one or more of’, e.g, “one or more of A, B, and/or

C” means “one or more of A”, “one or more of B”, “one or more of C”, “one or more of A and one or more of B”, “one or more of B and one or more of C”, “one or more of A and one or more of C” and “one or more of A, one or more of B, and one or more of C”.

[0123] As used herein, the phrase “consists essentially of’ in the context of a given ingredient in a composition, means that the composition may include additional ingredients so long as the additional ingredients do not adversely impact the activity, e.g, biological or pharmaceutical function, of the given ingredient. In the context of compositions comprising a modular therapeutic as disclosed herein, “consists essentially of’ means that the composition may comprise additional ingredients so long as they do not change the activity or function of the given modular therapeutic itself.

[0124] The phrase “comprises, consists essentially of, or consists of A” is used as a tool to avoid excess page and translation fees and means that in some embodiments the given thing at issue: comprises A, consists essentially of A, or consists of A. For example, the sentence “In some embodiments, the composition comprises, consists essentially of, or consists of A” is to be interpreted as if written as the following three separate sentences: “In some embodiments, the composition comprises A. In some embodiments, the composition consists essentially of A. In some embodiments, the composition consists of A.”

[0125] Similarly, a sentence reciting a string of alternates is to be interpreted as if a string of sentences were provided such that each given alternate was provided in a sentence by itself. For example, the sentence “In some embodiments, the composition comprises A, B, or C” is to be interpreted as if written as the following three separate sentences: “In some embodiments, the composition comprises A. In some embodiments, the composition comprises B. In some embodiments, the composition comprises C.” As another example, the sentence “In some embodiments, the composition comprises at least A, B, or C” is to be interpreted as if written as the following three separate sentences: “In some embodiments, the composition comprises at least A. In some embodiments, the composition comprises at least B. In some embodiments, the composition comprises at least C.”

[0126] To the extent necessary to understand or complete the disclosure of the present invention, all publications, patents, and patent applications mentioned herein are expressly incorporated by reference therein to the same extent as though each were individually so incorporated.

[0127] Having thus described exemplary embodiments of the present invention, it should be noted by those skilled in the art that the within disclosures are exemplary only and that various other alternatives, adaptations, and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.