Combination therapies comprising stabilized sars-cov-2 peptides

Abstract

Disclosed herein are methods of treating and / or preventing a coronavirus infection using a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent. Also provided herein are therapeutic combinations comprising a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent.

Description

COMBINATION THERAPIES COMPRISING STABILIZED SARS-COV-2PEPTIDESRELATED APPLICATIONS

[0001] This application claims priority to and benefit of U.S. Application No. 63 / 489,114, filed March 8, 2023, the entire contents of which are hereby incorporated by reference.SEQUENCE LISTING

[0002] A Sequence Listing conforming to the rules of WIPO Standard ST.26 is hereby incorporated by reference. Said Sequence Listing has been filed as an electronic document via PatentCenter encoded as XML in UTF-8 text. The electronic document, created on March 6, 2024, is entitled “406693-003WO_ST26.xml” and is 123,041 bytes in size.BACKGROUND

[0003] COVID-19 has been declared a high-risk global health emergency by the World Health Organization (WHO) and has, as of September 2022, caused 603,711,760 cases of respiratory disease and 6,484,136 deaths worldwide. Subsequent variants have posed an ongoing public health challenge, including thwarting the efficacy of vaccine, antibody, and molecular therapeutics.

[0004] SARS-CoV-2 contains a surface protein that undergoes a conformational change upon engagement with the host cell, resulting in formation of a six-helix bundle that brings the host and viral membranes together. Although peptide-based inhibition of viral fusion processes is mechanistically feasible and clinically effective (e.g., Fuzeon (i.e., enfurvirtide), approved by the FDA in 2003), the biophysical and pharmacologic liabilities of peptides, including loss of bioactive shape and rapid proteolysis in vivo (e.g., 100 mg self-injected twice daily), have limited broader application of this validated approach. Thus, new strategies for the preventing and / or treating COVID-19 infections are urgently required to effectively mitigate outbreaks.SUMMARY

[0005] The instant disclosure provides methods of treating and / or preventing a coronavirus infection comprising administering a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent. Also provided herein are therapeutic combinations comprising a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent. Thepeptides that bind to a SARS-CoV-2 spike protein used in the methods disclosed herein are particularly advantageous because they prevent coronavirus fusion to a host cell.

[0006] In an aspect, provided herein is a method of treating a coronavirus infection in a subj ect in need thereof, the method comprising administering to the subj ect: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0007] In an aspect, provided herein is a method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0008] In an aspect, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0009] In some embodiments, provided herein is a method of treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0010] In some embodiments, provided herein is a method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0011] In some embodiments, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0012] In some embodiments, provided herein is a method of treating a coronavirus infection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0013] In some embodiments, provided herein is a method of preventing a coronavirus infection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0014] In some embodiments, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0015] In an embodiment, the subject is a human, a cow, a pig, a horse, a cat, a dog, a rat, a mouse, a bat, a deer, a pangolin, a mink, a ferret, or a hamster.

[0016] In an embodiment, the subj ect is immune competent. In an embodiment, the subj ect is immunodeficient.

[0017] In an embodiment, the coronavirus is a betacoronavirus. In an embodiment, the coronavirus is SARS-CoV-2. In an embodiment, the coronavirus is a variant of SARS-CoV- 2. In an embodiment, the variant is selected from Wuhan-Hu-1, B.1.427 / B.1.429, B. 1.617.2, D614G B. l, Brazilian variant P.l, B. l.1.7, B.1.351, B.1.525, B.1.526, B. 1.617.1, B. l.617.3, P.2, B.l.621, B. 1.621.1, B.l.1.529, BA.l. BA.1.1, BA.2, BA.3, BA.4, or BA.5. In an embodiment, the variant is selected from B.1.351, Cluster 5, Lineage B. l. 1.207. Lineage B. l.1.7, Variant of Concern 202102 / 02, Lineage B. 1.1.317, Lineage B. l. 1.318, Lineage B.1.351, Lineage B. 1.429, Lineage B.1.525, Lineage P. l (also known as Lineage B. l. 1.28), Lineage B.1.1.529, Lineage BA. l, Lineage BA.1.1, Lineage BA.2, Lineage BA.3, Lineage BA.4 Lineage BAA, D614G, E484K, N501Y. S477G / N, or P681H.

[0018] In an aspect, provided herein is a therapeutic combination comprising a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0019] In an embodiment, the additional therapeutic agent is a vaccine, an antiviral agent, a monoclonal antibody, high-titer COVID- 19 convalescent plasma, an interferon, a protease inhibitor, a kinase inhibitor, or an immunomodulator.

[0020] In an embodiment, the additional therapeutic agent is an antiviral agent. In an embodiment, the antiviral agent is ritonavir-boosted nirmatrelvir, remdesivir, molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir. zanamivir, peramivir, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen, remdesivir.lopinavir, ritonavir, molnupiravir, or nirmatrelvir.

[0021] In an embodiment, the additional therapeutic agent is an immunomodulator. In an embodiment, the immunomodulator is a corticosteroid, an interleukin-6 inhibitor, an interleukin-1 inhibitor, a cytokine, ery thropoietin, thrombopoietin, a lymphotoxin (e.g., a tumor necrosis factor (TNF)), a hematopoietic factor such as interleukin (IL), a colony stimulating factor (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, or an immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomalidomide, avadomide, iberdomide, or a GSPTl degrader (e.g. CC-90009; MRT-2359)).

[0022] In an embodiment, the additional therapeutic agent is a monoclonal antibody. In an embodiment, the monoclonal antibody is tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, or sotrovimab.

[0023] In an embodiment, the additional therapeutic agent is an interferon. In an embodiment, the interferon is IFN-a, IFN-J3, or IFN-y.

[0024] In an embodiment, the additional therapeutic agent is a kinase inhibitor. In an embodiment, the kinase inhibitor is a JNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, a NAK inhibitor, an AKT inhibitor, a PI3K inhibitor, a RAK inhibitor, a MEK inhibitor, a MAPK inhibitor, or a CDK inhibitor.

[0025] In an embodiment, the peptide is at most 50 amino acids in length. In an embodiment, the peptide is 38 amino acids in length. In an embodiment, the peptide is or comprises a peptide of Formula (I):ZI or a pharmaceutically acceptable salt thereof, wherein: each Ri and R2 is H or a Ci to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted; each R3 is independently alkylene, alkenylene, or alkynylene. any of which is substituted or unsubstituted;z is 1, 2, 3, 4. 5, 6, 7, 8, 9, or 10; and each [Xaa]„ is DISGINASVVNIQ (SEQ ID NO: 35), each [Xaa]xis EIDRLN (SEQ ID NO: 36), and each [Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37).

[0026] In an embodiment, Ri is an alkyl. In an embodiment, Ri is a methyl group. In an embodiment, R2 is an alky l. In an embodiment, R2 is a methyl group. In an embodiment, R3 is an alkenylene.

[0027] In an embodiment, the peptide is or comprises a peptide of Formula I-A:or a pharmaceutically acceptable salt thereof;Rs is alkenylene;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0028] In an embodiment, the peptide is or comprises a peptide of Formula la:la or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I-A. and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0029] In an embodiment, the peptide is or comprises a peptide of the formula:or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I-A, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(0)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

[0030] In an embodiment, R3 is C7-15 alkenylene. In an embodiment, R3 is C9-13 alkenylene. In an embodiment, R3 is Cn alkenylene. In an embodiment, R3 is -(CH2)3-7-CH=CH-(CH2)3-7-. In an embodiment, R3 is -(CH2)5-7-CH=CH-(CH2)3-4-. In an embodiment, R3 is -(CH2)e- CH=CH-(CH2)3-.

[0031] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl). In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH3. In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0032] In an embodiment, the peptide further comprises PEG and / or a cholesterol. In an embodiment, the cholesterol is thiocholesterol. In an embodiment, the peptide further comprises PEG(n)-cholesterol, wherein the PEG(n)-cholesterol is conjugated to the N-terminus or C-terminus of the peptide, and wherein n is 1-36, optionally wherein n is 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36. In an embodiment, the peptide further comprises PEG(n)-thiocholesterol, wherein the PEG(n)-thiocholesterol is conjugated to the N-terminus or C-terminus of the peptide, and wherein n is 1-36, optionally wherein n is 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36.

[0033] In an embodiment, the peptide is a peptide of Formula II:or a pharmaceutically acceptable salt thereof, wherein:R3 is alkenylene;R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;Rs is hydrogen or C1-4 alkyl;Re is one of the following: alkyl). each of which is substituted by t occurrences of R?;R7 represents independently for each occurrence C1-3 alkyd, hydroxyl, or C1-3 alkoxyl;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and t is 0, 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0034] In an embodiment, the peptide is a peptide of Formula Ila:or a pharmaceutically acceptable salt thereof, wherein R3, R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula II, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0035] In an embodiment, the peptide is a peptide of formula:or a pharmaceutically acceptable salt thereof, wherein Rs, R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula II, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(0)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

[0036] In an embodiment, R3 is C7-15 alkenylene. In an embodiment, R3 is C9-13 alkenylene. In an embodiment, R3 is Cn alkenylene. In an embodiment, R3 is -(CH2)3-7-CH=CH-(CH2)3-7-. In an embodiment, R3 is -(CH2)5-7-CH=CH-(CH2)3-4-. In an embodiment, R3 is -(CH2)e- CH=CH-(CH2)3-.

[0037] In an embodiment, the peptide is a peptide of Formula III:or a pharmaceutically acceptable salt thereof, wherein:R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;R5 is hydrogen or C1.4 alkyl;Re is one of the following:each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyd, hydroxyl, or C1-3 alkoxyl;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p is 2, 3, 4, 5, 6, 7, or 8;z is 2, 3, 4, 5, or 6; and t is 0. 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0038] In an embodiment, the peptide is a peptide of Formula Illa:or a pharmaceutically acceptable salt thereof, wherein R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula III, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(0)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0039] In an embodiment, R4 is **-C(O)-(C2-3 alkylene)-[O-CH2CH2]m-N(R3)C(O)-(Ci-2 alkylene)-R6. wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y. In an embodiment, R4 is **-C(O)-(CH2CH2)-[O-CH2CH2]m- N(RS)C(O)-(CH2)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y.

[0040] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl). In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH2. In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0041] In an embodiment, the peptide is a peptide of Formula IV :or a pharmaceutically acceptable salt thereof, wherein:R4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alky lene)-Re;Rs is hydrogen or C1.4 alkyl;R6is one of the follow ing:each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl;Rs is -C(O)-(C 1.4 alkyl);[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. 15, or 16; p is 2, 3, 4. 5, 6, 7, or 8; z is 2, 3, 4, 5, or 6; and t is 0, 1, 2, or 3.

[0042] In an embodiment, the peptide is a peptide of Formula IVa:or a pharmaceutically acceptable salt thereof, wherein R4, Rs, [Xaa]w, [Xaa]x, [Xaa]z, p, and z are as defined above in Formula IV.

[0043] In an embodiment, the peptide is a peptide of Formula IVb:or a pharmaceutically acceptable salt thereof, wherein R4, Rs, [Xaa]w, [Xaa]x, and [Xaa]zare as defined above in Formula IV.

[0044] In an embodiment, the peptide is a peptide of Formula IVc:or a pharmaceutically acceptable salt thereof, wherein R4, Rs, [Xaa]w, [Xaa]x, and [Xaa]zare as defined above in Formula IV.

[0045] In an embodiment, the peptide is a peptide of Formula V:or a pharmaceutically acceptable salt thereof, whereinR4is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-R6;Rs is hydrogen or C1-4 alkyl;R6is one of the following:each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C 1-3 alkyl, hydroxyl, or C1-3 alkoxyl;Rs is -C(O)-(CM alkyl);[Xaa]wis DISGINASWNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and t is 0, 1, 2, or 3.

[0046] In an embodiment, R8is -C(O)CH3. In an embodiment, R4is -C(O)-(C2-3 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-2 alkylene)-R6. In an embodiment, R4is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)-R6. In an embodiment, R5 is hydrogen.

[0047] In an embodiment,substituted by t occurrences of R7.

[0048] In an embodiment,substituted by t occurrences of R7.

[0049] In an embodiment,substituted by t occurrences of R7.

[0050] In an embodiment,substituted by occurrences of R7.

[0051] In an embodiment,substituted by t occurrences of R7.

[0052] In an embodiment,substituted by t occurrences of R7.

[0053] In an embodiment, t is 0. In an embodiment, m is 4. In an embodiment, m is 8.

[0054] In an embodiment, the peptide is a peptide of Formula VI:or a pharmaceutically acceptable salt thereof, wherein[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77).

[0055] In an embodiment, the method increases viral clearance in the subject. In an embodiment, the method prevents new variants of SARS-CoV-2 in the subject.

[0056] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the treatment of a coronavirus infection in a subject in need thereof, according to the methods described herein.

[0057] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for thetreatment of a coronavirus infection in a subject in need thereof, according to the methods described herein.

[0058] In an aspect, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the treatment of a coronavirus infection in a subject in need thereof, according to the methods described herein.

[0059] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the prevention of a coronavirus infection in a subject in need thereof, according to the methods described herein.

[0060] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for the prevention of a coronavirus infection in a subject in need thereof, according to the methods described herein.

[0061] In an aspect, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the prevention of a coronavirus infection in a subject in need thereof, according to the methods described herein.100621 In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the methods described herein.

[0063] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the methods described herein.

[0064] In an aspect, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the methods described herein.BRIEF DESCRIPTION OF THE DRAWINGS

[0065] FIG. 1 depicts a mechanism of action of SARS-CoV-2 S fusion inhibitor peptides.

[0066] FIG. 2 provides the amino acid sequence of the S protein (SEQ ID NO: 1 ) of SARS-CoV-2.

[0067] FIG. 3 is a schematic representation of the SARS-CoV-2 spike (S) protein, including the sequence composition of the heptad repeat domain 1 (HR1) (SEQ ID NO: 2) and heptad repeat domain 2 (HR2) (SEQ ID NO: 3) fusion domains.

[0068] FIG. 4 shows an alignment of the HR1 and HR2 regions of SARS-CoV-2 andSARS-CoV-1 (“SARS, C.2004”) viruses highlighting the sequence homology, with striking sequence identity between the HR2 regions of SARS-CoV-2 and SARS-CoV-1 (SEQ ID NOs: 79 and 80).

[0069] FIG. 5 shows a variety of non-natural amino acids containing olefinic tethers that can be used to generate hydrocarbon stapled SARS-CoV-2 S peptides bearing staples spanning i, i+3; i, i+4; and i, i+7 positions. Single staple scanning is used to generate a library of singly stapled SARS-CoV-2- 19 HR2 peptides for conjugation to PEG-thiocholesterol or PEG- cholesterol moieties.

[0070] FIG. 6 shows a variety of staple compositions in multiply stapled peptides and staple scanning to generate a library of multiply stapled SARS-CoV-2 HR2 peptides for conjugation to PEG-thiocholesterol or PEG-cholesterol moieties.

[0071] FIG. 7 shows a variety of staple compositions in tandem stitched peptides to generate a library of stitched SARS-CoV-2 HR2 peptides for conjugation to PEG- thiocholesterol or PEG-cholesterol moieties.

[0072] FIG. 8 is an illustration of an exemplary approach to designing, synthesizing, and identifying optimal stapled peptide constructs to target the SARS-CoV-2 fusion apparatus, including the generation of Ala scan, staple scan, and variable N- and C-terminal deletion, addition, and derivatization libraries for conjugation to PEG-thiocholesterol or PEG- cholesterol moieties. Singly and doubly stapled and stitched constructs, including alanine and staple and stitch scans, are used to identify optimal stapled peptides for conjugation to PEG- thiocholesterol or PEG-cholesterol moieties and application in in vitro and in vivo analyses.

[0073] FIG. 9 is a helical wheel depiction of a portion of the SARS-CoV-2 HR2 domain structured as an amphipathic alpha-helix (SEQ ID NO: 4), illustrating the predominantly hydrophobic binding interface, with flanking charged or polar residues at the perimeter of the binding interface and at the non-interacting face. The arrow refers to the hydrophobic moment.

[0074] FIG. 10 shows a synthetic schema for converting thiocholesterol or cholesterol into a carboxylic acid for facile on-resin derivatization of stapled peptides with cholesterol- containing moieties. DCM: dichloromethane; TFA: trifluoroacetic acid.

[0075] FIG. 11A-11B shows a synthetic schema of the steps for on-resin derivatization of the stapled peptide sequence (SEQ ID NO: 74) with a PEG-linked thiocholesterol moiety (FIG. 11 A) and a synthetic schema of the steps for on-resin derivatization of the stapled peptide sequence (SEQ ID NO: 74) with a PEG-linked cholesterol moiety (FIG. 11B).

[0076] FIG. 12 shows exemplary unstapled (SEQ ID NOs: 5 and 6) and stapled SARS- CoV-2 HR2 peptide sequences (SEQ ID NOs: 7-21) generated by single i, i+7 staple scanningof a core template sequence (amino acids 1178-1199) bearing N- and C-terminal sequence extensions (e.g., amino acids 1168-1205) and C-terminal derivatization with PEG- thiocholesterol or PEG-cholesterol moieties of varying PEG linker length. 8 = (R)-a-(7'- octenyl)alanine; and X= (S)-a-(4'-pentenyl)alanine.

[0077] FIG. 13 shows that an unstapled HR2 sequence of SEQ ID NO: 5 exhibits no antiviral activity against the Wuhan-Hu- 1 fluorescent pseudovirus corresponding to GenBank QHD43416. 1, as measured by IXM microscopy. In contrast, C-terminal derivatization of SEQ ID NO: 5 with a PEG4-thiocholesterol moiety to produce the peptide of SEQ ID NO: 6 yields dose-responsive antiviral activity (pseudovirus: Wuhan-Hu-1; cells: 293T-ACE2; peptides: serial 2-fold dilution starting at 5 pM; read-out: 72 h).

[0078] FIG. 14 shows that a stapled HR2 peptide bearing a PEG4-thiocholesterol moiety appended on-resin (Staple D, SEQ ID NO: 10) exhibits consistent and potent anti-viral activity in the pseudovirus assay whether the cells were treated with peptide (1 pM) before or after viral inoculation across a series of SARS-CoV-2 pseudovirus variants. In contrast, the corresponding unstapled peptide (SEQ ID NO: 6) is ineffective when applied after viral inoculation and exhibits less anti-viral activity compared to the stapled sequence even when applied before viral inoculation with a series of SARS-CoV-2 pseudovirus variants (pseudovirus: D614G B.l, Wuhan-Hu-1, B.1.526, B.1.427 / B. 1.429, B. l. 1.7; cells: 293T- ACE2; read-out taken at 72 h).

[0079] FIG. 15 shows the differential antiviral activity of an unstapled and stapled HR2 peptides bearing a PEG4-thiocholesterol moiety appended on-resin, with peptide of SEQ ID NO: 10 (Staple D) showing the most potent dose-responsive anti-viral activity, followed by the unstapled peptide of SEQ ID NO: 6. The stapled peptide of SEQ ID NO: 17 (Staple K) was the least active in this pseudovirus assay (pseudovirus: B.1.526; cells: 293T-ACE2; serial 2-fold dilution starting at 1 pM; read-out: 72 h).

[0080] FIG. 16 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides bearing a PEG4-thiocholesterol moiety appended on-resin. Whereas peptides of SEQ ID NOs: 11, 14, and 15 (Staples E, H, I, respectively) show little to no activity and peptides of SEQ ID NOs: 13 and 16 (Staples G and J, respectively) exhibit moderate activity, the peptide of SEQ ID NO: 10 (Staple D) stands out as having uniquely potent activity among the various stapled HR2 peptides in the SARS-CoV-2 pseudovirus assay (pseudovirus: D614G B.l; cells: 293T-ACE2; peptide doses of 100, 300, 1000 nM; read-out at 48 h).

[0081] FIG. 17 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides bearing a PEG4-thiocholesterol moiety appended on-resin. Whereas peptides of SEQID NOs: 11, 14, and 15 (Staples E, H, I, respectively) show little to no activity (as measured by concentration of virus in pM on the X-axis) and peptides of SEQ ID NOs: 13 and 16 (Staples G and J) exhibit moderate activity, the peptide of SEQ ID NO: 10 (Staple D), consistent with the pseudovirus assays results shown in FIG. 15, stands out as having uniquely potent activity among the various stapled HR2 peptides in this SARS-CoV-2 live virus assay (live vims: USA- WA1 / 2020; cells: VeroB6; peptide dose-range 4-1000 nM (i.e., each group of bars, from bottom to top, represent a decreasing 2-fold dilution of peptide; i.e., 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM, 15.625 nM, 7.8125 nM, 3.90625 nM)).

[0082] FIGs. 18A-18B shows the differential antiviral activity of an i, i+7 staple scan of the indicated HR2 peptide sequence (SEQ ID NOs: 7-21) bearing a C-terminal PEG4- thiocholesterol moiety against SARS-CoV-2 (vims: live Beta strain; cells: VeroB6; peptide dose 4 pM), with the most active peptide sequences noted with an asterisk (FIG. 18A). A discrete subset of staple positions afford potent anti-viral activity (SEQ ID NOs: 10, 13, 17, 20), as summarized on a helical wheel depiction of the helical portion of the HR2 sequence (FIG. 18B).

[0083] FIG. 19 shows the antiviral activity of an i, i+7 stapled HR2 peptide of SEQ ID NO: 10 bearing a PEG4-thiocholesterol moiety against a GFP expressing SARS-CoV-2 Omicron variant B.1.1.529.1 (BAI) pseudovims (cells; 293T-ACE2 cells; peptide serial 2-fold dilution from 2000 nM; 48 h read-out).

[0084] FIG. 20 shows the antiviral activity of an i, i+7 stapled HR2 peptide of SEQ ID NO: 10 bearing a PEG4-thiocholesterol moiety against live SARS-CoV-2 beta and delta strains (cells: VeroB6; peptide dose-range 15-4000 nM (i.e., each group of bars, from bottom to top, represent a decreasing 2-fold dilution of peptide; i.e., 4000 nM, 2000 nM, 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM, 15.625 nM)).

[0085] FIG. 21 shows the antiviral activity of an i, i+7 stapled HR2 peptide of SEQ ID NO: 13 bearing a PEG4-thiocholesterol moiety, as measured against GFP-expressing SARS- CoV pseudovimses, including SARS-CoV-2 Wuhan-hu-1, SARS-CoV-2 Omicron BAI.1.529.1 (BAI), SARS-CoV-2 Omicron BAI. 1.529.2 (BA2), and SARS-CoV-1 (Urbani) (cells; 293T-ACE2 cells; peptide serial 2-fold dilution from 10 pM; 48 h read-out).

[0086] FIG. 22 shows the antiviral activity of an i, i+7 stapled HR2 peptide of SEQ ID NO:20 bearing a PEG4-thiocholesterol moiety, as measured against GFP-expressing SARS- CoV pseudovimses, including SARS-CoV-2 Wuhan-hu-1, SARS-CoV-2 Omicron BAI.1.529.1 (BAI), SARS-CoV-2 Omicron BAI. 1.529.2 (BA2), and SARS-CoV-1 (Urbani)(cells; 293T-ACE2 cells; peptide serial 2-fold dilution from 10 pM; 48 h read-out).

[0087] FIG. 23 shows the antiviral activity of i, i+7 stapled HR2 peptides of SEQ ID NO: 13 and SEQ ID NO: 20 bearing a PEG4-thiocholesterol moiety, as measured against live SARS-CoV-2 beta strain virus (cells: VeroB6; 4 pM dosing).

[0088] FIGs. 24A-24B shows a sequence map of an i, i+7 stapled HR2 peptide of SEQ ID NO: 10 (Staple D spanning positions KI 181 and El 188), highlighting the amino acid positions that are alternatively in contact with the HR1 core or unbound (solvent exposed) (SEQ ID NO: 81) (FIG. 24A). Mutagenesis studies revealed a series of exemplary positions that are relatively unaffected by substitution of the native residue with alanine, as assessed in the context of SEQ ID NO: 10 with a C-terminal PEG4 thiocholesterol moiety against GFP- expressing SARS-CoV-1 (Urbani) in a pseudovirus assay (cells; 293T-ACE2 cells; peptide 4- fold serial dilution from 1.25 pM; 48 h read-out) (FIG. 24B).

[0089] FIGs. 25A-25E shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides bearing a PEG-thiocholesterol moiety of variable PEG length (n = 3-8). The peptide of SEQ ID NO: 10 (Staple D) bearing a PEG8 linker moiety exhibits the most potent, dose-responsive activity in this pseudovirus assay across a series of five SARS-CoV-2 variants (as measured by number of green cells or percent GFP positive shown on the X-axis), with PEG3 having comparatively less activity among the constructs of variable PEG-linker length (pseudoviruses / variants: Wuhan-Hu-1 (FIG. 25A), B.1.427 / B. 1.429 (FIG. 25B), B. l.617.2 (FIG. 25C), D614G B.1(FIG. 25D), Brazilian variant P.l (FIG. 25E); cells: 293T-ACE2; serial 2-fold dilution starting at 1 pM (i.e., from bottom to top for each cluster of bars: 1 pM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM, 15.625 nM, 7.8125 nM); read-out: 48 h).

[0090] FIG. 26 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides bearing a PEG-thiocholesterol moiety of variable PEG length (n = 3-8) (Staple D, SEQ ID NO: 10). The peptide of SEQ ID NO: 10 (Staple D) bearing a PEG8 linker moiety exhibits the most potent, dose-responsive activity in this SARS-CoV-2 live virus assay, with PEG3 having comparatively less activity among the constructs of variable PEG-linker length (live virus: S. African B. 1.351; cells: VeroB6; peptide dose-range 4-1000 nM; i.e., serial 2-fold dilution, from bottom to top for each cluster of bars: 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.25 nM, 15.625 nM, 7.8125 nM, 3.90625 nM).

[0091] FIG. 27 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides of SEQ ID NO: 10 bearing a PEG-thiocholesterol moiety of variable PEG length (n = 0, 3-20), as measured against GFP expressing SARS-CoV-2 Omicron variant B. 1.1.529.1(BAI) (cells: 293T-ACE2; serial 3-fold dilution starting at 3.3 pM from bottom to top for each cluster of bars: 3.3 pM, 1.1 pM, 367 nM, 122 nM, 41 nM, 13 nM, 4.5 nM, 1.5 nM; read-out: 48 h).

[0092] FIG. 28 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides of SEQ ID NO: 10 bearing a PEG-thiocholesterol moiety of variable PEG length (n = 0, 3-20), as measured against GFP expressing SARS-CoV-1 (Urbani) (cells: 293T-ACE2; serial 2-fold dilution starting at 2 pM from bottom to top for each cluster of bars: 2 pM, 1 pM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.2 nM, 15.6 nM; read-out: 48 h).

[0093] FIG. 29 shows the differential antiviral activity of a series of i, i+7 stapled HR2 peptides of SEQ ID NO: 10 bearing a PEG-thiocholesterol moiety of variable PEG length (n = 0, 3-20), as measured against live SARS-CoV-2 Beta strain virus (cells: VeroB6; peptide doserange 7.8-1000 nM; i.e., serial 2-fold dilution, from bottom to top for each cluster of bars: 4000 nM, 2000 nM, 1000 nM, 500 nM, 250 nM, 125 nM, 62.5 nM, 31.2 nM, 15.6 nM, 7.8 nM).

[0094] FIG. 30 shows that the series of i, i+7 stapled HR2 peptides bearing a PEG- thiocholesterol moiety of variable PEG length (n = 3-8) (Staple D, SEQ ID NO: 10) exhibit no non-specific anti-viral activity against a Vesicular Stomatitis Virus (VSV) pseudovirus with murine leukemia virus (MLV) core, whereas the corresponding unstapled peptide (SEQ ID NO: 6) demonstrates some non-specific anti-viral activity (pseudovirus: VSV; cells: 293T-ACE2; peptides, 2.5 pM; read-out: 48 h).

[0095] FIG. 31 shows that an unstapled peptide derivatized with PEG4-thiocholesterol on resin (SEQ ID NO: 6) exhibits somewhat improved anti-viral activity compared to an unstapled peptide derivatized in solution with a GSGSGC-PEG4-cholesterol moiety (shown in SEQ ID NO:71) in this SARS-CoV-2 live virus assay (live virus: S. African B. 1.351; cells: VeroB6; peptide dose-range 4-1000 nM with two-fold dilutions).

[0096] FIG. 32 shows that an unstapled HR2 peptide (SEQ ID NO: 6) and a stapled HR2 peptide (SEQ ID NO: 10) derivatized with PEG4-thiocholesterol on resin show no non-specific cytotoxicity when applied to 293T-ACE2 cells in the pseudovirus assay, whereas the corresponding unstapled HR2 peptide derivatized in solution with a GSGSGC-PEG4- cholesterol moiety kills cells within the dosing range (pseudovirus: D614G B.l; cells: 293T- ACE2; serial 2-fold dilution starting at 2500 nM (from bottom to top, 2500 nM, 1250 nM, 630 nM, 315 nM, 158 nM, 78 nM); read-out: 48 h).

[0097] FIG. 33 shows a direct fluorescence polarization binding curve of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol and at the N-terminus with a FITC-P-Ala in place of the acetyl, combined with a serial dilution of a recombinant five-helix bundle (5HB)lacking the 3rdHR2 group. Addition of the FITC-HR2 peptide completes the fusogenic six helix bundle, (peptide: 5 nM; 5-HB protein serial dilution from 1000 nM).

[0098] FIG. 34 shows the differential antiviral activity of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol against a collection of GFP expressing SARS-CoV-2 variant pseudoviruses (293T-ACE2 cells; peptide serial dilution from 1000 nM; 48 h read-out).

[0099] FIG. 35 shows the differential antiviral activity of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol against GFP expressing SARS-CoV-2 Omicron variant pseudoviruses (293T-ACE2 cells; peptide serial dilution from 250 nM; 48 h read-out).

[0100] FIG. 36 shows the differential antiviral activity of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol against SARS-CoV-2 beta and delta live viruses (cells: Vero; peptide serial dilution from 100 nM serial dilution of peptide starting at 100 nM; 48 hour readout).

[0101] FIG. 37 shows the antiviral activity of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol against GFP expressing Alphacoronavirus NL63 pseudovirus (293T-ACE2 cells; peptide serial 3-fold dilution from 10 pM; 48 h read-out).DETAILED DESCRIPTION

[0102] The instant disclosure provides methods of treating and / or preventing a coronavirus infection comprising administering a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent. Also provided herein are therapeutic combinations comprising a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent. The peptides that bind to a SARS-CoV-2 spike protein used in the methods disclosed herein are particularly advantageous because they prevent coronavirus fusion to a host cell.Definitions

[0103] As used herein, the following definitions shall apply unless otherwise indicated. These definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Hence, the definition of “alkyl” applies to “alkyl” as well as the “alkyl” portions of “-O-alkyl” etc. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Smith, M.B. and March,J. (eds.), John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0104] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3.4-dihydro-27 / - yrrolyl). NH (as in pyrrolidinyl), or NR+(as in N- substituted pyrrolidinyl)).

[0105] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[0106] As used herein, the term “bivalent Cus (or Ci-e) saturated or unsaturated, straight or branched, hydrocarbon chain,” refers to bivalent alkylene, alkenylene, and alkynylene chains that are straight or branched as defined herein.

[0107] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3. from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0108] The term “-(Co alkylene)-” refers to a bond. Accordingly, the term “-(Co-3 alkylene)-” encompasses a bond (i.e., Co) and a -(C1-3 alkylene)- group.

[0109] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0110] The term “halogen” means F, CL Br, or I.

[0111] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,”“aralkoxy,” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring.” In an embodiment, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. The term“phenylene” refers to a multivalent phenyl group having the appropriate number of open valences to account for groups attached to it. For example, "‘phenylene” is a bivalent phenyl group when it has two groups attached to it (e lene” is a trivalent phenyl group when it has three groups attachedThe term “ary lene” refers to a multivalent (e g., bivalent) ary l group.

[0112] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms, preferably5, 6, or 9 ring atoms; having 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms “heteroaryl” and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where unless otherwise specified, the radical or point of attachment is on the heteroaromatic ring or on one of the rings to which the heteroaromatic ring is fused. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 / 7-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl group may be mono- or bicyclic. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0113] The term “heteroaiylene” refers to a multivalent heteroaryl group having the appropriate number of open valences to account for groups attached to it. For example, “heteroarylene” is a bivalent heteroaryl group when it has two groups attached to it; “heteroarylene” is a trivalent heteroaryl group when it has three groups attached to it.

[0114] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3.4-dihydro-27 / pyrrolyl). NH (as in pyrrolidinyl), or+NR (as in N- substituted pyrrolidinyl).

[0115] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, 2-oxa-6- azaspiro[3.3]heptane, and quinuclidinyl. The terms “heterocycle.” “heterocyclyl.” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H- -indolyl, chromanyl. phenanthridinyl. or tetrahydroquinolinyl. A heterocyclyl group may be mono- or bicyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “oxo-heterocyclyl” refers to a heterocyclyl substituted by one or more oxo group. The term “heterocyclylene” refers to a multivalent heterocyclyl group having the appropriate number of open valences to account for groups attached to it. For example, “heterocyclylene” is a bivalent heterocyclyl group when it has two groups attached to it; “heterocyclylene” is a trivalent heterocyclyl group when it has three groups attached to it. The term “oxo-heterocyclylene” refers to a multivalent oxo-heterocyclyl group having the appropriate number of open valences to account for groups attached to it.

[0116] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0117] As described herein, a molecule disclosed herein may contain ‘‘optionally substituted” moieties. In general, the term “substituted.” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned herein are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subj ected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0118] Each optional substituent on a substitutable carbon is a monovalent substituent independently selected from halogen; -(Cl [2)0 -4R0; -(Cl [2)04OR°; -0(CH2)o-4R°; -0-(CH2)o4C(O)OR°; -(CH2)O-4CH(OR0)2; -(CH2)OMSR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)O 40(CH2)O iPh which may be substituted with R°; -CH=CHPh, which may be substituted with R°; -(CH2)n lOfCTElo -1 -pyridyl which may be substituted with R°; -NO2; - CN; -N3; -(CH2)O4N(RO)2: -(CH2)O4N(RO)C(O)R°: -N(R°)C(S)R°: -(CH2)O4N(RO)C(O)NRO2; -N(RO)C(S)NR°2; -(CH2)OMN(R°)C(0)OR°;N(R°)N(R°)C(O)R°; -N(RO)N(RO)C(O)NRO2; -N(R°)N(R°)C(O)OR°; -(CH2)o4C(O)R°; - C(S)R°; -(CH2)o4C(0)0RO; -(CH2)OMC(0)SR°; -(CH2)O4C(O)OSIR°3; -(CH2)O4OC(O)R°; - OC(0)(CH2)O4SR; -(CH2)O4SC(O)RO; -(CH2)O4C(O)NRO2; -C(S)NRO2; -C(S)SR°; - SC(S)SR°; -(CH2)O4OC(O)NRO2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; - C(NOR°)R°; -(CH2)O4SSR°; -(CH2)O4S(O)2RO: -(CH2)O4S(O)2ORO; -(CH2)O4OS(O)2RO; - S(O)2NR°2; -S(O)(NR°)R°; -S(O)2N=C(NRO2)2; -(CH2)O4S(O)RO: -N(RO)S(O)2NRO2; - N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -OP(O)(OR°)2; -SIR°3; -(C IM straight or branched alkylene)O-N(R°)2; or -(CM straight or branched alkylene)C(O)O-N(R°)2.

[0119] Each R° is independently hydrogen. C1-6 aliphatic, -CEhPh, -0(CH2)o iPh, - CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atom(s). form a 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =0 and =S; or each R° is optionally substituted with a monovalent substituent independently selected from halogen, -(CH2)o2R*, -(haloR*), -(CH2)o20H, -(CH2)o20R*, - (CH2)O2CH(OR*)2, -O(haloR’). -CN, -N3, -(CH2)o2C(O)R*, -(CH2)o2C(O)OH, -(CH2)o-2C(O)OR*, -(CH2)O2SR*, -(CH2)O 2SH, -(CH2)O 2NH2, -(CH2)O 2NHR*. -(CH2)O 2NR’2, - N02, -SiR*3, -OSiR’s, -C(O)SR* -(Ci 4 straight or branched alkylene)C(O)OR*, or -SSR*.

[0120] Each R* is independently selected from Ci-4 aliphatic, -CH2Ph, 0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens; or wherein an optional substituent on a saturated carbon is a divalent substituent independently selected from =0, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, -O(C(R*2))2 3o- or -S(C(R’2))2-3S-, or a divalent substituent bound to vicinal substitutable carbons of an ■‘optionally substituted’’ group is -O(CR*2)23O-, wherein each independent occurrence of R* is selected from hydrogen, C 1 6 aliphatic or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0121] When R* is C1-6 aliphatic. R* is optionally substituted with halogen, - R*, -(haloR*), -OH, -OR’, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is independently selected from C1-4 aliphatic, -CH2Ph, -0(CH2)o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0122] An optional substituent on a substitutable nitrogen is independently -R1', -NR^, -C(O)Rf, -C(O)ORf, -C(O)C(O)Rf, -C(O)CH2C(O)Rt, -S(O)2R;’. -S(O)2NRt2, -C(S)NRf2, - C(NH)NRf2, or -N(R'f)S(O)2Rt; wherein each R1' is independently hydrogen, C1-6 aliphatic, unsubstituted -OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, two independent occurrences of R1', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or and mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R1' is C1-6 aliphatic, R1' is optionally substituted with halogen, R*. -(haloR*), -OH, -OR*, -O(haloR*), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or-NO2, wherein each R* is independently selected from CH aliphatic, -CH2Ph, -0(CH2)o iPh. or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R* is unsubstituted or where preceded by halo is substituted only with one or more halogens.

[0123] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds disclosed herein include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, buty rate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate. 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0124] Further, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al., Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley -VCH; S. Berge et al., Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould. International J. of Pharmaceutics (1986) 33 201-217; Anderson et al., The Practice of Medicinal Chemistry (1996), Academic Press, New' York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference.

[0125] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N (Ci -lalk lfi salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0126] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present molecules are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure. The disclosure includes compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures, including the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents.

[0127] Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, such as, for example, by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (c.g.. chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride), separating the diastereomers and converting (e.g, hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Alternatively, a particular enantiomer of a molecule disclosed herein may be prepared by asymmetric synthesis. Still further, where the molecule contains a basic functional group (such as amino) or an acidic functional group (such as carboxylic acid) diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means known in the art, and subsequent recovery of the pure enantiomers.

[0128] Individual stereoisomers of the molecules disclosed herein may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. Chiral center(s) in a molecule disclosed herein canhave the S or R configuration as defined by the IUPAC 1974 Recommendations. Further, to the extent a compound described herein may exist as an atropisomer (e.g., substituted biaryls), all forms of such atropisomer are considered part of this disclosure.

[0129] Chemical names, common names, and chemical structures may be used interchangeably to describe the same structure. If a chemical compound is referred to using both a chemical structure and a chemical name, and an ambiguity exists between the structure and the name, the structure predominates. It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples, and tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.

[0130] The terms “a” and “an” as used herein mean “one or more” and include the plural unless the context is inappropriate.

[0131] The term “alkyl” refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alky l, C1-C10 alkyl, and Ci-Ce alkyl, respectively. Exemplary alky l groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2 -methyl- 1 -propyl. 2-methy 1-2 -propyl, 2-methyl- 1-butyl, 3-methyl-l -butyl. 2-methyl-3-butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl. 3- methyl-1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-l-butyl, 2-ethy 1-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.

[0132] The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as “Cs-Ce cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include cyclohexyl, cyclopentyl, cyclobutyl, and cyclopropyl. The term “cycloalkylene” refers to a bivalent cycloalkyl group.

[0133] The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. Exemplary haloalkyl groups include -CH2F, -CHF2, -CF3, -CH2CF3, -CF2CF3, and the like. The term “haloalkylene” refers to a bivalent haloalkyl group.

[0134] The term “hydroxy alkyl” refers to an alkyl group that is substituted with at least one hydroxyl. Exemplary hydroxyalkyl groups include -CH2CH2OH, -C(H)(OH)CH3, -CH2C(H)(OH)CH2CH2OH, and the like.

[0135] The terms “alkenyl” and “alkynyl” are art-recognized and refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0136] The terms “alkoxy!” or “alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy! groups include methoxy, ethoxy, propyloxy, / e / 7-butoxy. and the like. The term “haloalkoxyl” refers to an alkoxyl group that is substituted with at least one halogen. Exemplary haloalkoxyl groups include -OCH2F, -OCHF2, -OCF3, -OCH2CF3, -OCF2CF3, and the like.

[0137] The term “oxo” is art-recognized and refers to a “=O” substituent. For example, a cyclopentane substituted with an oxo group is cyclopentanone.

[0138] The symbol “ ” indicates a point of attachment.

[0139] When any substituent or variable occurs more than one time in any constituent or the molecules disclosed herein, its definition on each occurrence is independent of its definition at every other occurrence, unless otherwise indicated.

[0140] One or more molecules disclosed herein may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the disclosure embrace both solvated and unsolvated forms. “Solvate” means a physical association of a molecule disclosed herein with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In an embodiment the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Nonlimiting examples of suitable solvates include ethanolates, methanolates, and the like. “Hydrate” is a solvate wherein the solvent molecule is H2O.

[0141] The term “IC50” is art-recognized and refers to the concentration of a compound that is required to achieve 50% inhibition of the target.

[0142] The term “EC50” is art recognized and refers to the concentration of a compound that is required to achieve a response that is 50% of the maximum target effect relative to the baseline.

[0143] The term “Emax” is art recognized and refers to the concentration of a compound that is required to achieve maximal target effect.

[0144] As used herein, the term “pharmaceutical composition” refers to the combination of an active agent with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.

[0145] As used herein, the term “pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g, such as an oil / water or water / oil emulsions), and various types of wettingagents. The compositions also can include stabilizers and preservatives. For examples of carriers, stabilizers, and adjuvants, see, e.g, Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA (1975).

[0146] For therapeutic use, salts of the molecules disclosed herein are contemplated as being pharmaceutically acceptable. However, salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0147] In addition, when a molecule disclosed herein contains both a basic moiety (such as, but not limited to, a pyridine or imidazole) and an acidic moiety (such as, but not limited to, a carboxylic acid) zwitterions (“inner salts'’) may be formed. Such acidic and basic salts used within the scope of the disclosure are pharmaceutically acceptable (i.e.. non-toxic, physiologically acceptable) salts. Such salts of the molecules disclosed herein may be formed, for example, by reacting a molecule disclosed herein with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

[0148] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions disclosed herein that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the disclosure that consist essentially of, or consist of, the recited processing steps.

[0149] As a general matter, compositions specifying a percentage are by weight unless otherwise specified.

[0150] As used herein, the term “effective amount'’ refers to the amount of a compound sufficient to effect beneficial or desired results (e.g, a therapeutic, ameliorative, inhibitory, or preventative result). An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route. As used herein, the term “treating” includes any effect, e.g.. lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.

[0151] As used herein, the term “subject” includes any human or non-human animal. In an embodiment, the subj ect is a human or non-human mammal. In an embodiment, the subj ect is a human.Anti-Coronavirus Peptides

[0152] In an aspect, provided herein is a method of treating a coronavirus infection in a subj ect in need thereof, the method comprising administering to the subj ect: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0153] In an aspect, provided herein is a method of preventing a coronavirus infection in a subj ect in need thereof, the method comprising administering to the subj ect: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0154] In an aspect, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0155] In an aspect, provided herein is a therapeutic combination comprising a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) an additional therapeutic agent.

[0156] Exemplary peptides that may be used in the methods or included in the therapeutic combinations disclosed herein are described in detail below.

[0157] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a stapled SARS-CoV-2 peptide based on a portion of the HR2 region. In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a SARS-CoV-2 peptide derived from SARS-CoV-2 HR2(ii68-i205) (DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGK (SEQ ID NO: 6)). In an embodiment, the stapled SARS-CoV-2 peptides derived from SEQ ID NO:9 include SAH- SARS-CoV-2-A; SAH-SARS-CoV-2-B; SAH-SARS-CoV-2-C; SAH-SARS-CoV-2-D; SAH- SARS-CoV-2-E; SAH-SARS-CoV-2-F; SAH-SARS-CoV-2-G; SAH-SARS-CoV-2-H; SAH- SARS-CoV-2-I; SAH-SARS-CoV-2-J; SAH-SARS-CoV-2-K; SAH-SARS-CoV-2-L; SAH- SARS-CoV-2-M; SAH-SARS-CoV-2-N; or SAH-SARS-CoV-2-0 (e.g., SEQ ID NOs: 7-21), as shown in Table 1 below.Table 1: Stapled SARS-CoV-2 HR2 Peptides.

[0158] In Table 1, “8” = (R)-a-(7'-octenyl)alanine; “X” = (S)-a-(4'-pentenyl)alanine; and* = PEG-thiocholesterol or PEG-chol esterol moiety. In an embodiment, * = the one of the twoformulae shown below, wherein n = 1-36 (n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23. 24, 25, 26, 27, 28, 29, 30. 31, 32, 33, 34, 35, or 36). In an embodiment, n = 4. In an embodiment, n = 8. The two formulae indicated by the include:

[0159] In some cases, the two formulae indicated by the include:

[0160] In an embodiment, the above peptides can be modified to include additional amino acids (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acids added) at the N and / or C-terminus, and / or to have N and / or C terminal deletions (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acids deleted). In an embodiment, the SARS-CoV-2 peptides are derived from SEQ ID NO:4.

[0161] Note that the bolded and underlined sequence used herein (e.g. , in Table 1) identifies the stapling amino acids at the N- and C-termini and the intervening sequencebetween staples for each disclosed peptide. In an embodiment, the peptide is a single-stapled peptide.

[0162] In an embodiment, SEQ ID NO: 6 includes one or more variants. For instance, if positions 25 or 29 of SEQ ID NO: 6 are substituted, they are substituted by an a, a-disubstituted non-natural amino acid with olefinic side chains or are substituted by any amino acid. In an embodiment, if one or more of positions 1, 2, 5, 7, 8, 10, 12, 16, 17, 19. 23. 24, 26, 28, 30, 31, 33. and 36 of SEQ ID NO: 6 are substituted, they are substituted by conservative amino acid substitutions. In an embodiment, if one or more of positions 3, 4, 6, 9, 1 1, 13, 15, 18, 20, 22, 27, 32, 34, 35, 37, or 38 in SEQ ID NO: 6 are substituted, they are substituted by any amino acid.

[0163] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is 19 to 50 (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) amino acids in length. In an embodiment, the peptide is 19 to 60 (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60) amino acids in length. In an embodiment, the peptide ranges from 19 to 100, 38 to 100. 19 to 60, 38 to 60, 19 to 50, 38 to 50, 19 to 45, 38 to 45, 19 to 40 and 38 to 40 amino acids in length. In an embodiment, the peptide described above have one or more (1, 2, 3, 4, 5, 6) of the properties listed below : (i) is alpha-helical; (ii) is protease resistant; (iii) inhibits fusion of SARS-CoV-2 with a host cell: and / or (iv) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide inhibits infection of a cell by SARS-CoV-2 in pseudovirus and / or live SARS-CoV-2 virus assays and / or wherein the peptide prevents infection of a cell by SARS- CoV-2 in the pseudovirus and / or the live SARS-CoV-2 virus assays.

[0164] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide includes an amino acid sequence that has 2 to 18, 2 to 17, 2 to 16, 2 to 15, 2 to 14, 2 to 13, 2 to 12, 2 to 11, 2 to 10, 2 to 9, 2 to 8, 2 to 7, 2 to 6, 2 to 5, 2 to 4, 2 to 3, or 2 substitutions, insertions, and / or deletions relative to SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 13. SEQ ID NO: 17, or SEQ ID NO:20. In an embodiment, a peptide having substitutions, insertions, and / or deletions relative to SEQ ID NO: 6, SEQ ID NO: 10, SEQ ID NO: 13. SEQ ID NO: 17, or SEQ ID NO: 20 as described above (i) is alpha-helical; (ii) is protease resistant; (iii) inhibits fusion of SARS-CoV-2 with a host cell; and / or (iv) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide inhibits infection of a cell by SARS-CoV-2 in pseudo virus and / or live SARS-CoV-2 virus assays and / or wherein the peptide prevents infection of a cell by SARS-CoV-2 in the pseudovirus and / or the live SARS-CoV-2 virusassays. In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.

[0165] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide comprises 0-10 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions compared to one of the single-stapled peptides (e.g., SEQ ID NOs: 7-21) in Table 1. In an embodiment, the peptide is at least 75% (e.g., at least 75%, at least 80%, at least 85%. at least 90%, at least 94%, at least 95% identical) to one of the single-stapled peptides (e.g., SEQ ID NOs: 7-21) in Table 1 . In an embodiment, the peptide is 19 to 50 (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) amino acids in length. In an embodiment, the peptide is 19 to 60 (e.g., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45. 46. 47. 48. 49. 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60) amino acids in length. In an embodiment, the peptide ranges from 19 to 100, 38 to 100, 19 to 60, 38 to 60, 19 to 50, 38 to 50, 19 to 45, 38 to 45, 19 to 40 and 38 to 40 amino acids in length. In an embodiment, the peptide has one or more (1, 2, 3, 4, 5, 6) of the properties listed below: (i) is alpha-helical; (ii) is protease resistant; (iii) inhibits fusion of SARS-CoV-2 with a host cell: and / or (iv) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide inhibits infection of a cell by SARS-CoV-2 in pseudovirus and / or live SARS-CoV-2 virus assays and / or wherein the peptide prevents infection of a cell by SARS- CoV-2 in the pseudovirus and / or the live SARS-CoV-2 virus assays. In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.

[0166] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide comprises or consists of any one of the amino acid sequences of SEQ ID NOs: 5 or 6, except that at least two (e.g., 2, 3, 4, 5, 6) amino acids of SEQ ID NOs: 5 or 6 are replaced with a non-natural amino acid capable of forming a staple. In an embodiment, the non-natural amino acid is an a, a-disubstituted non-natural amino acid with at least one olefinic side chain. In an embodiment, the peptide is a peptide comprising or consisting of any one of the amino acid sequences of SEQ ID NOs: 5 or 6, except that at least two (e.g., 2, 3, 4, 5, 6) amino acids of SEQ ID NOs: 5 or 6 are replaced with anon-natural amino acid capable of forming a staple. In an embodiment, the non-natural amino acid is an a, a-disubstituted non-natural amino acid with at least one olefinic side chain. In an embodiment, the peptide is 19 to 50 (e.g., 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) amino acids in length. In an embodiment, the peptide is 19 to 60 (e.g., 36, 37, 38. 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60) amino acids in length. In an embodiment, the peptide ranges from 19 to 100, 38 to 100, 19 to 60, 38 to 60, 19 to 50, 38 to 50, 19 to 45, 38 to 45, 19 to 40 and 38to 40 amino acids in length. In an embodiment, the peptide has one or more (1, 2, 3, 4, 5, 6) of the properties listed below: (i) is alpha-helical; (ii) is protease resistant; (iii) inhibits fusion of SARS-CoV-2 with a host cell; and / or (iv) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide inhibits infection of a cell by SARS-CoV-2 in pseudovirus and / or live SARS-CoV-2 virus assays and / or wherein the peptide prevents infection of a cell by SARS- CoV-2 in the pseudovirus and / or the live SARS-CoV-2 virus assays. In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.

[0167] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide comprises 0-10 (0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) amino acid substitutions compared to one of the unmodified peptides (e.g., SEQ ID NOs: 5 or 6) in Table 1. In an embodiment, disclosed herein are peptides that are at least 75% (e.g., at least 75%. at least 80%. at least 85%, at least 90%, at least 95% identical) to one of the unmodified peptides (e.g., SEQ ID NOs: 5 or 6) in Table 1. In an embodiment, the substitution as described herein is a conservative substitution. In an embodiment, the peptide is 19 to 50 (e.g., 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) amino acids in length. In an embodiment, the peptide is 19 to 60 (e.g., 36. 37. 38. 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60) amino acids in length. In an embodiment, the peptide ranges from 19 to 100, 38 to 100, 19 to 60, 38 to 60, 19 to 50, 38 to 50, 19 to 45, 38 to 45, 19 to 40 and 38 to 40 amino acids in length. In an embodiment, the peptide described above have one or more (1, 2, 3, 4, 5, 6) of the properties listed below: (i) is alpha-helical; (ii) is protease resistant; (iii) inhibits fusion of SARS-CoV-2 with a host cell; and / or (iv) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide inhibits infection of a cell by SARS-CoV-2 in pseudovirus and / or live SARS-CoV-2 virus assays and / or wherein the peptide prevents infection of a cell by SARS- CoV-2 in the pseudo virus and / or the live SARS-CoV-2 virus assays. In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.

[0168] In an embodiment, any substitution as described herein can be a conservative substitution. In an embodiment, any substitution as described herein is a non-conservative substitution.

[0169] In an embodiment, the non-natural amino acids that may be used as stapling amino acids are: (R)-2-(2'-propenyl)alanine; (R)-2-(4'-pentenyl)alanine; (R)- a -(7'-octenyl)alanine; (S)-a-(2'-propenyl)alanine; (S)-a-(4'-pentenyl)alanine; (S)-2-(7'-octenyl)alanine; a,a-Bis(4'- pentenyl)glycine; and a,a-Bis(7'-octeny)glycine.

[0170] In some embodiments, an internal staple replaces the side chains of 2 amino acids, i.e., each staple is between two amino acids separated by, for example, 6 ammo acids. In someembodiments, the amino acids forming the staple are at each of positions i and i+7 of the staple. For example, where a peptide has the sequence . . . XI, X2, X3. X4, X5, X6, X7. X8, X9 . . . , cross-links between XI and X8 (i and i+7) are useful hydrocarbon stapled forms of that peptide. The use of an i and i+4 staple, multiple cross-links (e.g., 2, 3, 4, or more), or a tandem stitch is also contemplated. Additional description regarding making and use of hydrocarbon-stapled peptides can be found, e.g., in U.S. Patent Publication Nos. 2012 / 0172285, 2010 / 0286057, and 2005 / 0250680. the contents of all of which are incorporated by reference herein in their entireties.

[0171] “Peptide stapling” is a term coined from a synthetic methodology wherein two olefm-containing side-chains (e.g., cross-linkable side chains) present in a peptide chain are covalently joined (e.g., “stapled together”) using a ring-closing metathesis (RCM) reaction to form a cross-linked ring (see, e.g, Blackwell et al., J. Org. Chem., 66: 5291-5302, 2001; Angew et al., Chem. Int. Ed. 37:3281, 1994). The structural-stabilization may be by, e.g., stapling the peptide (see, e.g., Walensky, J. Med. Chem., 57:6275-6288 (2014), the contents of which are incorporated by reference herein in its entirety). In some cases, the staple is a hydrocarbon staple.

[0172] In an embodiment, a staple used herein is a lactam staple; a UV-cycloaddition staple; an oxime staple; a thioether staple; a double-click staple; a bis-lactam staple; a bis-arylation staple; or a combination of any two or more thereof. Stabilized peptides as described herein include stapled peptides as well as peptides containing multiple staples or any other chemical strategies for structural reinforcement (see. e.g., Balaram P. Cur. Opin. Struct. Biol. 1992:2:845; Kemp DS, et al.. J. Am. Chem. Soc. 1996;118:4240; Omer BP, et al., J. Am. Chem. Soc. 2001;123:5382; Chin JW, et al., Int. Ed. 2001;40:3806; Chapman RN, et al.. J. Am. Chem. Soc. 2004;126: 12252; Home WS, et al., Chem., Int. Ed. 2008;47:2853; Madden et al.. Chem Commun (Camb). 2009 Oct 7; (37): 5588-5590; Lau et al., Chem. Soc. Rev., 2015,44:91-102; and Gunnoo et al., Org. Biomol. Chem., 2016,14:8002-8013; each of which is incorporated by reference herein in its entirety).

[0173] A peptide is “structurally-stabilized” in that it maintains its native secondary structure. For example, stapling allows a peptide, predisposed to have an a-helical secondary structure, to maintain its native a-helical conformation. This secondary structure increases resistance of the peptide to proteolytic cleavage and heat, and may increase target binding affinity, hydrophobicity, plasma membrane binding, and / or cell permeability. Accordingly, the stapled (cross-linked) peptides described herein have improved biological activity and pharmacology relative to a corresponding non-stapled (un-cross-linked) peptide.

[0174] In an embodiment, the modification(s) to introduce structural stabilization (e.g , internal cross-linking, e.g. , stapling) into the SARS-CoV-2 HR2 peptides described herein may be positioned on the face of the SARS-CoV-2 HR2 helix that does not interact with the recombinant 5-helix bundle of SARS-CoV-2 or corresponding native fusion apparatus. Alternatively, the modification(s) to introduce stabilization (e.g, internal cross-linking, e.g , stapling) into the SARS-CoV-2 HR2 peptides described herein may be positioned on the face of the SARS-CoV-2 HR2 helix that does interact with the 5-helix bundle of SARS-CoV-2. In some cases, a SARS-CoV-2 HR2 peptide described herein is stabilized by introducing a staple (e.g, a hydrocarbon staple) at the interface of the interacting and non-interacting helical faces of the SARS-CoV-2 HR2 protein. In some cases, a SARS-CoV-2 HR2 peptide described herein is stabilized by introducing a staple (e.g. . a hydrocarbon staple) or staples at the border between the hydrophobic interacting surface and the non-interacting faces of the SARS-CoV-2 HR2 protein.

[0175] In an embodiment, the modifications to introduce structural stabilization (e.g., internal cross-linking, e g , stapling) into the SARS-CoV-2 HR2 peptides included in the methods and therapeutic combinations disclosed herein are positioned at the ammo acid positions in the SARS-CoV-2 HR2 peptide corresponding to residues:(i) 11 and 18 of SEQ ID NO: 6;(ii) 12 and 19 of SEQ ID NO: 6;(iii) 13 and 20 of SEQ ID NO: 6;(iv) 14 and 21 of SEQ ID NO: 6;(v) 15 and 22 of SEQ ID NO: 6;(vi) 16 and 23 of SEQ ID NO : 6;(vii) 17 and 24 of SEQ ID NO : 6;(vm) 18, and 25 of SEQ ID NO: 6;(ix) 19 and 26 of SEQ ID NO: 6;(x) 20 and 27 of SEQ ID NO: 6;(xi) 21 and 28 of SEQ ID NO: 6;(xii) 22 and 29 of SEQ ID NO: 6;(xiii) 23 and 30 of SEQ ID NO: 6;(xiv) 24 and 31 of SEQ ID NO: 6; or(xv) 25 and 32 of SEQ ID NO: 6.

[0176] In an embodiment of the methods and therapeutic combinations disclosed herein, the SARS-CoV-2 HR2 peptides described herein (e.g., SEQ ID NOs: 5 or 6) may also containone or more (e.g., 1, 2, 3, 4, or 5) amino acid substitutions (relative to an amino acid sequence set forth in any one of SEQ ID NOs: 5 or 6), e.g.. one or more (e.g., 1, 2, 3. 4, or 5) conservative and / or non-conservative amino acid substitutions. In an embodiment, the SARS-CoV-2 HR2 peptides included in the methods and therapeutic combinations disclosed herein (e.g., SEQ ID NOs: 5 or 6) may also contain at least one, at least 2, at least 3, at least 4, or at least 5 amino acids added to the N-terminus of the peptide. In an embodiment, the SARS-CoV-2 HR2 peptides included in the methods and therapeutic combinations disclosed herein (e.g., SEQ ID NOs: 5 or 6) may also contain at least one, at least 2, at least 3, at least 4, or at least 5 amino acids added to the C-terminus of the peptide.

[0177] In an embodiment, the N-terminal aspartic acid in any one of the peptides included in the methods and therapeutic combinations disclosed herein is replaced with -N(H)C(O)-(Ci- 4 alkyl). In an embodiment, the carboxylic acid group of the C-terminal lysine in any one of the peptides included in the methods and therapeutic combinations disclosed herein is replaced with C(O)NH2. In an embodiment, the N-terminal aspartic acid in SEQ ID NO: 6, SEQ ID NO: 10. or SEQ ID NO:20 is replaced with -N(H)C(O)-(CI-4 alkyl). In an embodiment, the carboxylic acid group of the C-terminal lysine in SEQ ID NO: 6. SEQ ID NO: 10. SEQ ID NO: 13, SEQ ID NO: 17, or SEQ ID NO:20 is replaced with C(O)NH2.

[0178] In an embodiment, the C-terminal lysine of any of the peptides included in the methods and therapeutic combinations disclosed herein is replaced with ornithine (e.g., L- omithine), L-2,3-diaminopropionic acid, L-2.7-diaminoheptanoic acid, diamino butyric acid (e.g., L-2,4-diamino butyric acid), an amino acid having an alpha carbon amine, or a diamine.

[0179] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is or comprises a peptide of Formula (I):Formula (I) or a pharmaceutically acceptable salt thereof, wherein: each Ri and R2 are independently H or a Ci to C10 alky l, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;R3 is alkyl, alkenyl, alkynyl, or [R4 — K — R4]n; each of which is substituted with 0-6 R5;R4IS alkyl, alkenyl, or alkynyl;Rs is halo, alkyl, ORe, N(Re)2, SRe, SORe. SO2R6. CO2Re. Re. a fluorescent moiety, or a radioisotope;Re is H, alkyl, or a therapeutic agent; n is an integer from 1-4; x is an integer from 2-10; each y is independently an integer from 0-100; z is an integer from 1-10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10); and each Xaa is independently an amino acid.

[0180] In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.

[0181] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is or comprises a peptide of Formula (I-A):I-A or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I.

[0182] In an embodiment, the peptide consists of Formula (I-A).

[0183] In an embodiment, R3 of Formula (I-A) is alkenylene. In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with - C(O)NH2.

[0184] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is or comprises a peptide of Formula la:la or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I.

[0185] In one embodiment, the peptide consists of Formula (la).

[0186] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wof Formula (la) is replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0187] In an embodiment, the peptide comprises or consists of:Formula (Id). or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I.

[0188] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C- terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0189] In an embodiment, R3 of any one of Formula (I)-(Id) (i.e., I, la, lb, Ic, Id) is C7-15 alkenylene. In an embodiment, R3 is C9-13 alkenylene. In an embodiment, R3 is Cn alkenylene.In an embodiment, R3 is -(CH2)3-7-CH=CH-(CH2)3-7-. In an embodiment, R3 is -(042)5-7- CH=CH-(CH2)3-4-. In an embodiment, R3 is -(CH2)6-CH=CH-(CH2)3-.

[0190] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(FI)C(O)-(CI-4 alkyl). In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH3. In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0191] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula II:or a pharmaceutically acceptable salt thereof, wherein:R3 is alkenylene;R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;Rs is hydrogen or C1-4 alkyl;Re is one of the following:, each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1.3 alkyl, hydroxyl, or C1.3 alkoxyl;[Xaajw is DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14. 15. or 16; and t is 0. 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]„ is replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0192] In an embodiment. R3 of Formula II is alkenylene. In an embodiment, R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-R6. wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y. In an embodiment Rs is hydrogen or C1.4 alkyl.

[0193] In an embodiment, Re is one of the following: alkyl), optionally wherein each of which is substituted by t occurrences of R7.

[0194] In an embodiment, R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl. In an embodiment, m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In an embodiment, t is 0, 1, 2, or 3.

[0195] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C- terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0196] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula Ila:Formula Ila or a pharmaceutically acceptable salt thereof, wherein R3, R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula II, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl). In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0197] In an embodiment, the peptide comprises or consists of:Formula (lib),Formula (II d), or a pharmaceutically acceptable salt thereof, wherein Rs, R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula II, and wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(0)-(CI-4 alkyl). In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl). In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with - C(O)NH2.

[0198] In an embodiment, Rs of Formula (II), (Ila), (lib), (lie), or (lid) is C7-15 alkenylene. In an embodiment, Rs is C9-13 alkenylene. In an embodiment, R3 is C11 alkenylene. In an embodiment, R3 is -(CH2)3-7-CH=CH-(CH2)s-7-. In an embodiment, R3 is -(CH2)s-7-CH=CH- (CH2)S-4-. In an embodiment, R3 is -(CH2)6-CH=CH-(CH2)s-.

[0199] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula III:[Xaa]y R4[Xaa]w— N s}- ^ ijC ||H ’ z oPFormula (III) or a pharmaceutically acceptable salt thereof, wherein:R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;Rs is hydrogen or C1-4 alkyl;Rs is one of the following:alkyl), each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p is 2, 3, 4, 5, 6, 7, or 8; z is 2, 3, 4, 5, or 6; and t is 0. 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in |Xaa|» is replaced with -N(H)C(O)-(C 1-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0200] In an embodiment. R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-R6. wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y.

[0201] In an embodiment, R5 is hydrogen or C 1-4 alkyd. In an embodiment, Re is one of the following: alkyl), optionally wherein each of which is substituted by t occurrences of R7.

[0202] In an embodiment, R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl. In an embodiment, m is 3, 4. 5, 6, 7. 8, 9, 10, 11, 12, 13, 14, 15, or 16. In an embodiment, p is 2, 3, 4, 5, 6, 7, or 8. In an embodiment, z is 2, 3, 4, 5, or 6. In an embodiment, t is 0, 1, 2, or 3. In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyd). In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0203] In an embodiment of the methods and therapeutic combinations disclosed herein,the peptide is a peptide of Formula (Illa):or a pharmaceutically acceptable salt thereof, wherein R4, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above in Formula III.

[0204] In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C- terminal lysine in [Xaa]yis replaced with -C(O)NH2. In an embodiment, R4 is **-C(O)-(C2-3 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-2 alkylene)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y. In an embodiment. R4 is **-C(O)-(CH2CH2)-[O-CH2CH2]m-N(Rs)C(O)-(CH2)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y. In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with - N(H)C(O)-(CI-4 alkyl). In an embodiment, the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH3. In an embodiment, the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

[0205] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula (IV):or a pharmaceutically acceptable salt thereof, wherein:R4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alky lene)-R6;R5 is hydrogen or C1.4 alkyl;R6is one of the following:alkyl), each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl;Rs IS -C(O)-(C 1.4 alkyl);[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p is 2, 3, 4, 5, 6, 7, or 8; z is 2, 3, 4, 5, or 6; and t is 0, 1, 2, or 3.

[0206] In an embodiment, R4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(Rs)C(O)-(Ci-6 alkylene)-R6. In an embodiment, R5 is hydrogen or C1-4 alky l. In an embodiment, Re is one of the following: alkyl)optionally wherein each of which is substituted by t occurrences of R7.

[0207] In an embodiment, R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl. In an embodiment. Rs is -C(O)-(Ci-4 alkyl). In an embodiment, m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In an embodiment, p is 2, 3, 4, 5, 6, 7, or 8. In an embodiment, z is 2, 3, 4, 5, or 6. In an embodiment, t is 0, 1, 2, or 3.

[0208] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula IVa:Formula (I Va),or a pharmaceutically acceptable salt thereof, wherein R4. Rs, [Xaa]w, [Xaa]x, [Xaa]z, p, and z are as defined above for Formula IV.

[0209] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula IVb:or a pharmaceutically acceptable salt thereof, wherein R4, Rs, [Xaa]w, [Xaa]x, and [Xaa]zare as defined above for Formula IV.

[0210] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula IVc:or a pharmaceutically acceptable salt thereof, wherein R4, Rs, [Xaa]w, [Xaa]x, and [Xaa]zare as defined above for Formula IV.

[0211] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula V :or a pharmaceutically acceptable salt thereof, wherein:R4 is -C(O)-(C2-e alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alky lene)-Re;Rs is hydrogen or C1.4 alkyl;R6is one of the following:alkyl), each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyd, hydroxyl, or C1-3 alkoxyl;Rs is -C(O)-(C 1.4 alkyl);[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and t is 0, 1, 2, or 3.

[0212] In an embodiment, R4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re. In an embodiment, Rs is hydrogen or C1-4 alkyl. In an embodiment. Re is one of the following: alkyl), optionally wherein each of which is substituted by t occurrences of R7.

[0213] In an embodiment, R7 represents independently for each occurrence C1-3 alkyd, hydroxyl, or C1-3 alkoxyl. In an embodiment, Rs is -C(O)-(Ci-4 alkyl). In an embodiment, [Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35); [Xaa]xis EIDRLN (SEQ ID NO: 36); and [Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77). In an embodiment, m is 3, 4, 5. 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. In an embodiment, t is 0, 1, 2, or 3.

[0214] In an embodiment, Rs is -C(O)CH3. In an embodiment, R4 is -C(O)-(C2-3 alkylene)- [O-CH2CH2]m-N(R5)C(O)-(Ci-2 alkylene)-R6. In an embodiment, R4 is -C(O)-(CH2CH2)-[O- CH2CH2]m-N(R5)C(O)-(CH2)-R6. In an embodiment. Rs is hydrogen. In an embodiment. Re alkyl)substituted by t occurrences of R7.

[0215] In an embodiment,occurrences of R7.

[0216] In an embodiment,occurrences of R7.

[0217] In an embodiment,occurrences ofR.7.

[0218] In an embodiment,occurrences of R7.

[0219] In an embodiment.occurrences of R7.

[0220] In an embodiment, wherein t is 0. In an embodiment, m is 4. In an embodiment, m is 8.

[0221] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula VI:EIDRLN (SEQ ID NO: 36); and [Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77).

[0224] In an embodiment, each of the [Xaa]wof Formula (I), the [Xaa]xof Formula (I), and the [Xaa]yof Formulae (I), (la), (II), (Ila), is as described for any one of constructs 1-15 of Table 2. For example, for a peptide comprising the [Xaa]w, the [Xaa]x, and the [Xaa]yof construct 1 of Table 2, the [Xaa]w, the [Xaa]x, and the [Xaa]yis: DISGINASVV (SEQ ID NO:26), IQKEID (SEQ ID NO: 27), and LNEVAKNLNESLIDLQELGK (SEQ ID NO: 28), respectively. As another example, for a stabilized peptide comprising the [Xaa]w, the [Xaa]x, and the [Xaa]yof construct 2 of Table 2, the [Xaa]w, the [Xaa]x, and the [Xaa]yis: DISGINASVVN (SEQ ID NO: 29), QKEIDR (SEQ ID NO: 30), and NEVAKNLNESLIDLQELGK (SEQ ID NO: 31), respectively.Table !. [Xaa] [Xaa] x, and [Xaa]ysequences for Formula (I) constructs 1-15.

[0225] In an embodiment, the sequences set forth above in Table 2 have at least one (e.g., 1 , 2, 3, 4, 5, or 6) amino acid substitution or deletion. The SARS-CoV-2 HR2 peptides can include any amino acid sequence described herein.

[0226] In an embodiment, the peptide of Formula (I) comprising the sequences set forth above in Table 2 has one or more of the properties listed below: (i) binds the recombinant SARS-CoV-2 5-helix bundle S protein and / or the corresponding native fusion apparatus; (ii) is alpha-helical; (iii) is protease resistant; (iv) inhibits fusion of SARS-CoV-2 with a host cell; and / or (v) inhibits infection of a cell by SARS-CoV-2. In an embodiment, the peptide binds to a polypeptide comprising or consisting of the sequence of SEQ ID NO:78.|00227] The tether of Formula (I) can include an alkyl, alkenyl, or alkynyl moiety (e.g., Cs, Cs, Ci i, or C12 alkyl, a Cs, Cs, or Cn alkenyl, or Cs, Cs, Cn, or C12 alkynyl). The tethered amino acid can be alpha disubstituted (e.g., C1-C3 or methyl).

[0228] In an embodiment of Formula (I), x is 2, 3, or 6. In an embodiment of Formula (I), each y is independently an integer between 0 and 15, or 3 and 15. In an embodiment of Formula (I), Ri and R2 are each independently H or Ci-Ce alkyl. In an embodiment of Formula (I), Ri and R2 are each independently C1-C3 alkyl. In an embodiment or Formula (I), at least one of Ri and R2 are methyl. For example, Ri and R2 can both be methyl. In an embodiment of Formula (I), R3 is alkyl (e.g., Cs alkyl) and x is 3. In an embodiment of Formula (I), R3 is Cn alkyl and x is 6. In an embodiment of Formula (1), R3 is alkenyl (e.g., Cs alkenyl) and x is 3. In an embodiment of Formula (I), x is 6 and R3 is Ci 1 alkenyl. In an embodiment, R3 is a straight chain alkyl, alkenyl, or alkynyl. In an embodiment, R3 is — CH2 — CH2 — CH2 — CH=CH — CTI2 - CH2— CH2— .

[0229] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: each Ri and R2is H or a Ci to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted; each R3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted; z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and(a) each [Xaa]wis DISGINASVV (SEQ ID NO: 26), each [Xaa]xis IQKEID (SEQ ID NO: 27), and each [Xaa]yis LNEVAKNLNESLIDLQELGK (SEQ ID NO: 28);(b) each [Xaa]wis DISGINASVVN (SEQ ID NO: 29), each [Xaa]xis QKEIDR (SEQ ID NO: 30), and each [Xaa]yis NEVAKNLNESLIDLQELGK (SEQ ID NO: 31);(c) each [Xaa]wis DISGINASVVNI (SEQ ID NO: 32), each [Xaa]xis KEIDRL (SEQ ID NO: 33), and each [Xaa]yis EVAKNLNESLIDLQELGK (SEQ ID NO: 34);(d) each [Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35), each [Xaa]xis EIDRLN (SEQ ID NO: 36), and each [Xaa]yis VAKNLNESLTDLQELGK (SEQ ID NO: 37);(e) each [Xaa]wis DISGINASWNIQK (SEQ ID NO: 38), each [Xaa]xis IDRLNE (SEQ ID NO: 39), and each [Xaa]yis AKNLNESLIDLQELGK (SEQ ID NO: 40);(!) each [Xaa]wis DISGINASVVNIQKE (SEQ ID NO: 41), each [Xaa]xis DRLNEV (SEQ ID NO: 42), and each [Xaa]yis KNLNESLIDLQELGK (SEQ ID NO: 43);(g) each [Xaa]wis DISGINASVVNIQKEI (SEQ ID NO: 44), each [Xaa]xis RLNEVA (SEQ ID NO: 45), and each [Xaa]yis NLNESLIDLQELGK (SEQ ID NO: 46);(h) each [Xaa]wis DISGINASVVNIQKEID (SEQ ID NO: 47), each [Xaa]xis LNEVAK (SEQ ID NO: 48), and each [Xaa]yis LNESL1DLQELGK (SEQ ID NO: 49);(i) each [Xaa]wis DISGINASVVNIQKEIDR (SEQ ID NO: 50), each [Xaa]xis NEVAKN (SEQ ID NO: 51), and each [Xaa]yis NESLIDLQELGK (SEQ ID NO: 52);(j) each [Xaa]wis DISGINASVVNIQKEIDRL (SEQ ID NO: 53), each [Xaa]xis EVAKNL (SEQ ID NO: 54), and each [Xaa]yis ESLIDLQELGK (SEQ ID NO: 55);(k) each [Xaa]wis DISGINASVVNIQKEIDRLN (SEQ ID NO: 56), each [Xaa]xis VAKNLN (SEQ ID NO: 57), and each [Xaa]yis SLIDLQELGK (SEQ ID NO: 58);(l) each [Xaa]wis DISGINASVVNIQKEIDRLNE (SEQ ID NO: 59), each [Xaa]xis AKNLNE (SEQ ID NO: 60), and each [Xaa]yis LIDLQELGK (SEQ ID NO: 61);(m) each [Xaa]wis DISGINASVVNIQKEIDRLNEV (SEQ ID NO: 62), each [Xaa]xis KNLNES (SEQ ID NO: 63), and each [Xaa]yis IDLQELGK (SEQ ID NO: 64);(n) each [Xaa]wis DISGINASVVNIQKEIDRLNEV A (SEQ ID NO: 65), each [Xaa]xis NLNESL (SEQ ID NO: 66), and each [Xaa]yis DLQELGK (SEQ ID NO: 67); or(o) each [Xaa]wis DISGINASVVNIQKEIDRLNEVAK (SEQ ID NO: 68), each [Xaa]xis LNESLI (SEQ ID NO: 69), and each [Xaa]yis LQELGK (SEQ ID NO: 70).

[0230] In an embodiment, wherein Ri is an alkyl. In an embodiment, Ri is a methyl group. In an embodiment, R3 is an alkyl. In an embodiment, R3 is a methyl group. In an embodiment, R2 is an alkenyl. In an embodiment, z is 1.

[0231] In another aspect of Formula (I), the two alpha, alpha disubstituted stereocentersare both in the R configuration or S configuration (e.g., i, i+4 cross-link), or one stereocenter is R and the other is S (e.g., i, i+7 cross-link). Thus, where Formula (I) is depicted as:z the C’ and C” disubstituted stereocenters can both be in the R configuration, or they can both be in the S configuration. In some embodiments, when x is 6 in Formula (I), the C’ disubstituted stereocenter is in the R configuration and the C” disubstituted stereocenter is in the S configuration. In some embodiments, the R3 double bond of Formula (I) can be in the E or Z stereochemical configuration.

[0232] In an embodiment of Formula (I), R3 is [R4 — K — R4]n; and R4 is a straight chain alkyl, alkenyl, or alkynyl.

[0233] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide comprising the amino acid sequence of any one of SEQ ID NOs: 6 or 7 (or a modified version thereof), wherein: the side chains of two amino acids separated by six amino acids are replaced by an internal staple.

[0234] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide is a peptide that is 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or 100 amino acids in length. In an embodiment, the peptide is 19-45 amino acids (i.e., 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45) in length. In an embodiment, the peptide is 36-45 amino acids (i.e., 36, 37, 38, 39, 40, 41, 42, 43, 44, or 45) in length. In an embodiment, the peptide is 38-45 amino acids (i.e., 38, 39, 40, 41, 42, 43, 44, or 45) in length. In an embodiment, the peptide is 36-42 amino acids (i.e., 36,37, 38, 39, 40, 41, 42) in length. In an embodiment, the peptide is 38-42 amino acids (i.e., 38, 39, 40, 41, 42) in length. In an embodiment, the peptide is 36 amino acids in length. In an embodiment, the peptide is 38 amino acids in length. Exemplary COVID- 19 HR2 peptides are shown in Table 1 and described in Formula (I). In an embodiment, the peptide comprises or consists of a stapled version of the amino acid sequence of any one of SEQ ID NOs: 7-21 (e.g. , the product of a ring-closing metathesis reaction performed on a peptide comprising the aminoacid sequence of any one of SEQ ID NOs: 7-21, respectively). In one embodiment, the peptide comprises or consists of a stapled version of the amino acid sequence of SEQ ID NO: 5 (e.g., the product of a ring-closing metathesis reaction performed on a peptide comprising the amino acid sequence of SEQ ID NO: 5). In one embodiment, the peptide comprises or consists of a stapled version of the amino acid sequence of SEQ ID NO: 6 (e.g. , the product of a ring-closing metathesis reaction performed on a peptide comprising the amino acid sequence of SEQ ID NO: 6).

[0235] In an embodiment, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 11 and 18 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 12 and 19 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 13 and 20 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 14 and 21 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 15 and 22 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 16 and 23 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 17 and 24 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 18 and 25 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 19 and 26 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 20 and 27 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 21 and 28 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 22 and 29 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are atthe amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 23 and 30 of SEQ ID NO: 6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 24 and 31 of SEQ ID NO:6. In certain embodiments, the two amino acids each separated by six amino acids are at the amino acid positions in the SARS-CoV-2 HR2 peptide corresponding to positions 25 and 32 of SEQ ID NO:6.

[0236] While hydrocarbon tethers are provided herein, other tethers can also be employed in the peptides described herein. For example, the tether can include one or more of an ether, thioether, ester, amine, amide, or triazole moiety. In some cases, a naturally occurring amino acid side chain can be incorporated into the tether. For example, a tether can be coupled with a functional group such as the hydroxyl in serine, the thiol in cysteine, the primary amine in lysine, the acid in aspartate or glutamate, or the amide in asparagine or glutamine. Accordingly, it is possible to create a tether using naturally occurring amino acids rather than using a tether that is made by coupling two non-naturally occurring amino acids. It is also possible to use a single non-naturally occurring amino acid together with a naturally occurring amino acid. Triazole-containing (e.g., 1, 4 triazole or 1, 5 triazole) crosslinks can be used (see, e.g., Kawamoto et al. 2012 Journal of Medicinal Chemistry 55: 1137; WO 2010 / 060112). In addition, other methods of performing different types of stapling are well known in the art and can be employed with the SARS-CoV-2 HR2 peptides described herein (see, e.g., Lactam stapling'. Shepherd et al., J. Am. Chem. Soc., 127:2974-2983 (2005); UV-cycloaddition stapling'. Madden et al., Bioorg. Med. Chem. Lett., 21 : 1472-1475 (2011); Disulfide stapling-. Jackson et al., Am. Chem. Soc., 113 :9391-9392 (1991); Oxime stapling-. Haney et al., Chem. Commun., 47: 10915-10917 (2011); Thioether stapling-. Brunel and Dawson, Chem. Commun., 552-2554 (2005); Photoswitchable stapling-. J. R. Kumita et al., Proc. Natl. Acad. Sci. U. S. A., 97:3803-3808 (2000); Double-click stapling-. Lau et al., Chem. Sci., 5: 1804-1809 (2014); Bis-lactam stapling-. J. C. Phelan et al.„ J. Am. Chem. Soc., 119:455-460 (1997); and Bis- arylation stapling-. A. M. Spokoyny et al., J. Am. Chem. Soc., 135:5946-5949 (2013)).

[0237] It is further envisioned that the length of the tether can be varied. For instance, a shorter length of tether can be used where it is desirable to provide a relatively high degree of constraint on the secondary alpha-helical structure, whereas, in an embodiment, it is desirable to provide less constraint on the secondary alpha-helical structure, and thus a longer tether may be desired.

[0238] Additionally, while tethers spanning from amino acids i to i+7 are provided herein in order to provide a tether that is primarily on a single face of the alpha helix, the tethers canbe synthesized to span any combinations of numbers of amino acids and also used in combination to install multiple tethers.

[0239] In an embodiment, the hydrocarbon tethers (i.e., cross links) described herein can be further manipulated. In one instance, a double bond of a hydrocarbon alkenyl tether, (e.g. , as synthesized using a ruthenium-catalyzed ring closing metathesis (RCM)) can be oxidized (e.g., via epoxidation, aminohydroxylation or dihydroxylation) to provide one of compounds below:

[0240] Either the epoxide moiety or one of the free hydroxyl moieties can be further functionalized. For example, the epoxide can be treated with a nucleophile, which provides additional functionality that can be used, for example, to attach a therapeutic agent. Such derivatization can alternatively be achieved by synthetic manipulation of the amino or carboxy terminus of the peptide or via the amino acid side chain. Other agents can be attached to the functionalized tether, e.g., an agent that facilitates entry of the peptide into cells.

[0241] In an embodiment, alpha disubstituted amino acids are used in the peptide to improve the stability of the alpha helical secondary stmcture. However, alpha disubstituted amino acids are not required, and instances using mono-alpha substituents (e.g., in the tethered amino acids) are also envisioned.

[0242] In an embodiment, the peptides can further comprise a drug, a toxin, a derivative of polyethylene glycol; a second peptide; a carbohydrate, etc.

[0243] The addition of polyethelene glycol (PEG) molecules can improve the pharmacokinetic and pharmacodynamic properties of the peptide. For example, PEGylation can reduce renal clearance and can result in a more stable plasma concentration. PEG is a water-soluble polymer and can be represented as linked to the peptide as formula:XO— CH2CH2O)n— CH2CH2-Y where n is 2 to 10,000 and X is H or a terminal modification, e.g., a Ci-4 alkyl; and Y is an amide, carbamate or urea linkage to an amine group (including but not limited to, the epsilon amine of lysine or the N-terminus) of the peptide. Y may also be a maleimide linkage to a thiol group (including but not limited to, the thiol group of cysteine).

[0244] Other methods for linking PEG to a peptide, directly or indirectly, are known tothose of ordinary skill in the art. The PEG can be linear or branched. Various forms of PEG including various functionalized derivatives are commercially available.

[0245] PEG as used herein functions as a linker or spacer between one of the peptides and a cholesterol or thiocholesterol moiety. In an embodiment, the PEG molecule comprises the following formula, wherein n = 1-36 (n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36):

[0246] In an embodiment, the PEG molecule comprises the following formula, wherein n= 1-36 (n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36):

[0247] In an embodiment, the PEG molecule comprises the following formula, wherein n = 1-36 (n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36):

[0248] In an embodiment, the PEG molecule comprises the following formula, wherein n = 1-36 (n = 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36):

[0249] In an embodiment for each of the formulae above, n = 4. In an embodiment for each of the formulae above, n = 5. In an embodiment for each of the formulae above, n = 6. In an embodiment for each of the formulae above, n = 7. In an embodiment for each of the formulae above, n = 8.

[0250] In an embodiment, the PEG molecule includes a cholesterol moiety. In an embodiment, the cholesterol moiety is thiocholesterol. In an embodiment, the sulfur of the thioether moiety in thiocholesterol is replaced by an oxygen atom to produce an ether moiety in the cholesterol derivatization.

[0251] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptide comprises PEG and / or cholesterol. In an embodiment, the cholesterol is thiocholesterol. In an embodiment, the peptide further comprises PEG(n)-cholesterol, wherein the PEG(n)-cholesterol is conjugated to the N-terminus or C-terminus of the peptide, and wherein n is 1-36, optionally wherein n is 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36. In an embodiment, the peptide further comprises PEG(n)-thiocholesterol, wherein the PEG(n)-thiocholesterol is conjugated to the N-terminus or C-terminus of the peptide, and wherein n is 1-36, optionally wherein n 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36.

[0252] PEG having degradable linkages in the backbone can be used. For example, PEG can be prepared with ester linkages that are subject to hydrolysis. Conjugates having degradable PEG linkages are described in WO 99 / 34833; WO 99 / 14259, and U.S. 6,348,558.

[0253] In certain embodiments, the PEG is attached to a peptide described herein through an intermediate linker. In certain embodiments, the linker is made up of from 1 to 20 amino acids linked by peptide bonds, wherein the amino acids are selected from the 20 naturally occurring amino acids. Some of these amino acids may be glycosylated, as is well understood by those in the art. In other embodiments, the 1 to 20 amino acids are selected from glycine, alanine, proline, asparagine, glutamine, and lysine. In other embodiments, a linker is made up of a majority of amino acids that are sterically unhindered, such as glycine and alanine. Nonpeptide linkers are also possible. For example, alkyl linkers such as -NH(CH2)nC(O)-,wherein n = 2-20 can be used. These alkyl linkers may further be substituted by any non- sterically hindering group such as lower alkyl (e.g, Ci-Ce). lower acyl, halogen (e.g., Cl, Br), CN, NH2, phenyl, etc. U.S. Pat. No. 5,446,090 describes a bifunctional PEG linker and its use in forming conjugates having a peptide at each of the PEG linker termini.

[0254] In an embodiment of the methods and therapeutic combinations disclosed herein, the peptides are further modified, e.g.. to further facilitate mucoadhesion, membrane binding, or increase in vivo stability. For example, acylating or PEGylating a peptide increases bioavailability, increases blood circulation, alters pharmacokinetics, alters immunogenicity, and / or decreases the needed frequency of administration.

[0255] In some embodiments, the peptides disclosed herein have an enhanced ability to bind to or penetrate cell membranes (e.g , relative to non-stapled peptides). See, e.g. , International Publication No. WO 2017 / 147283, which is incorporated by reference herein in its entirety.Therapeutic Combinations

[0256] In an aspect, provided herein is a therapeutic combination comprising a therapeutically effective amount of a) a peptide that binds to a SARS-CoV-2 spike protein; and b) an additional therapeutic agent.

[0257] In an embodiment, the therapeutic combination comprises a therapeutically effective amount of a) any one of the peptides described above; and b) an additional therapeutic agent.

[0258] In an embodiment, the additional therapeutic agent is a protease inhibitor. In an embodiment, the protease inhibitor is camostat mesylate, nafamostat mesylate, bromhexine hydrochloride, lopinavir. or ritonavir.

[0259] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:whereinR4IS -C(O)-(CH2CH2)-[O-CH2CH2]8-N(H)C(O)-(CH2)-R6;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a protease inhibitor selected from the group consisting of camostat mesylate, nafamostat mesylate, bromhexine hydrochloride, lopinavir. or ritonavir.

[0260] In an embodiment, the additional therapeutic agent is a vaccine. In an embodiment, the vaccine is mRNA-1273, AZD-1222, BNT162, CoronaVac, NVX-CoV 2372, SCB-2019, ZyCoV-D, or CoVaxin.

[0261] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a vaccine selected from the group consisting of mRNA-1273, AZD-1222, BNT162, CoronaVac, NVX-CoV 2372. SCB-2019, ZyCoV-D. or CoVaxin.

[0262] In an embodiment, the additional therapeutic agent is a vaccine, an antiviral agent, a monoclonal antibody, high-titer COVID- 19 convalescent plasma, an interferon, a protease inhibitor, a kinase inhibitor, or an immunomodulator.

[0263] In an embodiment, the additional therapeutic agent is an antiviral agent. In an embodiment, the antiviral agent is ritonavir-boosted nirmatrelvir, remdesivir, molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir. zanamivir, peramivir, acyclovir, valacyclovir. penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen. remdesivir. lopinavir, ritonavir, molnupiravir, or nirmatrelvir.

[0264] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is an antiviral agent selected from the group consisting of ritonavir-boosted nirmatrelvir, remdesivir, molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir, zanamivir, peramivir, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen, remdesivir, lopinavir, ritonavir, molnupiravir, and nirmatrelvir.

[0265] In an embodiment, the additional therapeutic agent is an immunomodulator. In an embodiment, the immunomodulator is a corticosteroid, an interleukin-6 inhibitor, an interleukin-1 inhibitor, a cytokine, erythropoietin, thrombopoietin, a lymphotoxin (e g., atumor necrosis factor (TNF)), a hematopoietic factor such as interleukin (IL), a colony stimulating factor (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, or an immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomalidomide, avadomide, iberdomide, or a GSPTl degrader (e.g. CC-90009; MRT-2359)).

[0266] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is an immunomodulator selected from the group consisting of a corticosteroid, an interleukin-6 inhibitor, an interleukin- 1 inhibitor, a cytokine, erythropoietin, thrombopoietin, a lymphotoxin (e.g., a tumor necrosis factor (TNF)), a hematopoietic factor such as interleukin (IL), a colony stimulating factor (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, or an immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomalidomide, avadomide, iberdomide, and a GSPTl degrader (e.g. CC-90009; MRT-2359)).

[0267] In an embodiment, the additional therapeutic agent is a monoclonal antibody. In an embodiment, the monoclonal antibody is tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, or sotrovimab.

[0268] In an embodiment of any one of the therapeutic combinations disclosed herein, thepeptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a monoclonal antibody selected from the group consisting of tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, and sotrovimab.

[0269] In an embodiment, the additional therapeutic agent is an interferon. In an embodiment, the interferon is IFN-a, IFN-[3. or IFN-y.

[0270] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:whereinR4IS -C(O)-(CH2CH2)-[O-CH2CH2]8-N(H)C(O)-(CH2)-R6;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is IFN-a, IFN-P, or IFN-y.

[0271] In an embodiment, the additional therapeutic agent is a kinase inhibitor. In an embodiment, the kinase inhibitor is a JNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, a NAK inhibitor, an AKT inhibitor, a PI3K inhibitor, a RAK inhibitor, a MEK inhibitor, a MAPK inhibitor, or a CDK inhibitor.

[0272] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a kinase inhibitor selected from the group consisting of aJNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, aNAK inhibitor, an AKT inhibitor, a PI3K inhibitor, a RAK inhibitor, a MEK inhibitor, a MAPK inhibitor, and a CDK inhibitor.

[0273] In an embodiment of any one of the therapeutic combinations disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is selected from the group consisting of remdesivir, nafamostat, favilavir. bamlanivimab, bancitinib, hydroxychloroquine / chloroquine, casirivimab and imdevimab, PTC299, leronlimab, bamlanivimab, lenzilumab, ivermectin, RLF-100 (aviptadil), metformin, AT-527, tocilizumab, niclosamide, convalescent plasma, famotidine, lopinavir- ritonavir, infliximab, AZD7442, AZD7442, CT-P59, heparin, VIR-7831, JS016, sarilumab, CD24Fc. adalimumab, STI-1499, dexamethasone, PB1046, galidesivir. bucillamine. PF- 00835321 (PF-07304814), apixaban, lanadelumab, hydrocortisone, canakinumab, colchicine, BLD-2660, gelsolin, MK-4482, TXA127, lapilimod dimesylate, SAR443122, ABX464, AdMSCs, losmapimod, mavrilimumab, and acalabmtinib.

[0274] In an embodiment, the additional therapeutic agent is an antibiotic. In an embodiment, the antibiotic is a macrolide antibiotic, including azithromycin, clarithromycin, erythromycin, or roxithromycin. In an embodiment, the antibiotic is amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin.Methods of Treatment

[0275] In an aspect, provided herein is a method of treating a coronavirus infection in a subj ect in need thereof, the method comprising administering to the subj ect: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0276] In an aspect, provided herein is a method of preventing a coronavirus infection in a subj ect in need thereof, the method comprising administering to the subj ect: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0277] In an aspect, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

[0278] In some embodiments, provided herein is a method of treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0279] In some embodiments, provided herein is a method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0280] In some embodiments, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

[0281] In some embodiments, provided herein is a method of treating a coronavirus infection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0282] In some embodiments, provided herein is a method of preventing a coronavirusinfection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0283] In some embodiments, provided herein is a method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

[0284] In an embodiment, the subject is a human, a cow, a pig, a horse, a cat, a dog, a rat, a mouse, a bat. a deer, a pangolin, a mink, a ferret, or a hamster.

[0285] In an embodiment, the subj ect is immune competent. In an embodiment, the subj ect is immunodeficient.

[0286] In an embodiment, the coronavirus is a betacoronavirus. In an embodiment, the coronavirus is SARS-CoV-2. In an embodiment, the coronavirus is a variant of SARS-CoV- 2. In an embodiment, the variant is selected from Wuhan-Hu-1, B.1.427 / B.1.429. B. 1.617.2, D614G B. l, Brazilian variant P.l, B. l.1.7, B.1.351, B.1.525, B.1.526, B. 1.617.1, B. l.617.3, P.2, B.l.621, B. 1.621.1, B.l.1.529, BA.l, BA.1.1, BA.2, BA.3, BA.4, or BA.5. In an embodiment, the variant is selected from B.1.351, Cluster 5, Lineage B. l. 1.207, Lineage B. l.1.7, Variant of Concern 202102 / 02, Lineage B. 1.1.317. Lineage B. l. 1.318. Lineage B.1.351, Lineage B. 1.429, Lineage B.1.525, Lineage P. l (also known as Lineage B. l. 1.28), Lineage B.1.1.529, Lineage BA. l, Lineage BA.1.1, Lineage BA.2, Lineage BAA, Lineage BA.4 Lineage BAA, D614G, E484K, N501Y, S477G / N, or P681H.

[0287] In an aspect, provided herein is a therapeutic combination comprising a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) an additional therapeutic agent.

[0288] In an embodiment, the additional therapeutic agent is a vaccine, an antiviral agent, a monoclonal antibody, high-titer COVID- 19 convalescent plasma, an interferon, a protease inhibitor, a kinase inhibitor, or an immunomodulator.

[0289] In an embodiment, the additional therapeutic agent is a protease inhibitor. In an embodiment, the protease inhibitor is camostat mesylate, nafamostat mesylate, bromhexine hydrochloride, lopinavir, or ritonavir.

[0290] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a protease inhibitor selected from the group consisting of camostat mesylate, nafamostat mesylate, bromhexine hydrochloride, lopinavir, or ritonavir.

[0291] In an embodiment, the additional therapeutic agent is a vaccine. In an embodiment, the vaccine is mRNA-1273, AZD-1222, BNT162, CoronaVac, NVX-CoV 2372, SCB-2019, ZyCoV-D, or CoVaxin.

[0292] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:whereinR4is -C(O)-(CH2CH2)-[O-CH2CH2]8-N(H)C(O)-(CH2)-R6;[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a vaccine selected from the group consisting of mRNA-1273, AZD-1222, BNT162, CoronaVac. NVX-CoV 2372. SCB-2019, ZyCoV-D. or CoVaxin.

[0293] In an embodiment, the additional therapeutic agent is an antiviral agent. In an embodiment, the antiviral agent is ritonavir-boosted nirmatrelvir, remdesivir, molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir, zanamivir, peramivir, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen. remdesivir. lopinavir, ritonavir, molnupiravir, or nirmatrelvir.

[0294] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); andthe additional therapeutic agent is an antiviral agent selected from the group consisting of ritonavir-boosted nirmatrelvir. remdesivir. molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir, zanamivir, peramivir, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen, remdesivir, lopinavir, ritonavir, molnupiravir, and nirmatrelvir.

[0295] In an embodiment, the additional therapeutic agent is an immunomodulator. In an embodiment, the immunomodulator is a corticosteroid, an interleukin-6 inhibitor, an interleukin-1 inhibitor, a cytokine, erythropoietin, thrombopoietin, a lymphotoxin (e g., a tumor necrosis factor (TNF)), a hematopoietic factor such as interleukin (IL), a colony stimulating factor (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, or an immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomalidomide, avadomide, iberdomide, or a GSPTl degrader (e.g. CC-90009; MRT-2359)).

[0296] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaajz is VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is an immunomodulator selected from the group consisting of a corticosteroid, an interleukin-6 inhibitor, an interleukin- 1 inhibitor, a cytokine, ery thropoietin, thrombopoietin, a lymphotoxin (e g., a tumor necrosis factor (TNF)), a hematopoietic factorsuch as interleukin (IL), a colony stimulating factor (e.g.. granulocyte-colony stimulating factor (G-CSF). granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, or an immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomahdomide, avadomide, iberdomide, and a GSPTl degrader (e.g. CC-90009; MRT-2359)).

[0297] In an embodiment, the additional therapeutic agent is a monoclonal antibody. In an embodiment, the monoclonal antibody is tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, or sotrovimab.

[0298] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a monoclonal antibody selected from the group consisting of tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, and sotrovimab.

[0299] In an embodiment, the additional therapeutic agent is an interferon. In an embodiment, the interferon is IFN-a, IFN-(3. or IFN-y.

[0300] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is IFN-a, IFN-P, or IFN-y.

[0301] In an embodiment, the additional therapeutic agent is a kinase inhibitor. In an embodiment, the kinase inhibitor is a JNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, a NAK inhibitor, an AKT inhibitor, a PI3K inhibitor, a RAK inhibitor, a MEK inhibitor, a MAPK inhibitor, or a CDK inhibitor.

[0302] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:whereinR4is -C(O)-(CH2CH2)-[O-CH2CH2]8-N(H)C(O)-(CH2)-R6;[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is a kinase inhibitor selected from the group consisting of a JNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, a NAK inhibitor, an AKT inhibitor, aPI3K inhibitor, a RAK inhibitor, aMEK inhibitor, a MAPK inhibitor, and a CDK inhibitor.

[0303] In an embodiment, the additional therapeutic agent is remdesivir. nafamostat, favilavir, bamlanivimab, baricitinib, hydroxychloroquine / chloroquine, casirivimab and imdevimab, PTC299, leronlimab, bamlanivimab, lenzilumab, ivermectin, aviptadil, metformin, AT-527, tocilizumab, niclosamide, convalescent plasma, famotidine, lopinavir-ritonavir, infliximab, AZD7442, AZD7442, CT-P59, heparin, VIR-7831, JS016, sarilumab, CD24Fc, adalimumab, STI-1499, dexamethasone. PB1046, galidesivir. bucillamine, PF-00835321 (PF- 07304814). apixaban, lanadelumab, hydrocortisone, canakinumab. colchicine. BLD-2660, gelsolin, MK-4482, TXA127, lapilimod dimesylate, SAR443122, ABX464, AdMSCs, losmapimod, mavrilimumab, or acalabmtinib.

[0304] In an embodiment of any one of the methods disclosed herein, the peptide is a peptide of the following formula:whereinR4is -C(O)-(CH2CH2)-[O-CH2CH2j8-N(H)C(O)-(CH2)-R6;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); and the additional therapeutic agent is selected from the group consisting of remdesivir, nafamostat, favilavir. bamlanivimab, baricitinib, hydroxychloroquine / chloroquine, casirivimab and imdevimab, PTC299, leronlimab, bamlanivimab, lenzilumab, ivermectin, aviptadil, metformin, AT-527, tocilizumab, niclosamide, convalescent plasma, famotidine, lopinavir-ritonavir, infliximab, AZD7442, AZD7442, CT-P59, heparin, VIR-7831, JS016, sarilumab, CD24Fc, adalimumab, STI-1499, dexamethasone. PB1046. galidesivir. bucillamine, PF-00835321 (PF- 07304814), apixaban, lanadelumab, hydrocortisone, canakinumab, colchicine, BLD-2660, gelsolin, MK-4482, TXA127, lapilimod dimesylate, SAR443122, ABX464, AdMSCs, losmapimod, mavrilimumab, and acalabmtinib.

[0305] In an embodiment, the additional therapeutic agent is an antibiotic. In an embodiment, the antibiotic is a macrolide antibiotic, including azithromycin, clarithromycin, erythromycin, or roxithromycin. In an embodiment, the antibiotic is amoxicillin, doxycycline, cephalexin, ciprofloxacin, clindamycin, metronidazole, sulfamethoxazole, trimethoprim, amoxicillin, clavulanate, or levofloxacin.

[0306] In an embodiment, the additional therapeutic agent is an immunosuppressant. In an embodiment, the immunosuppressant is a calcineurin inhibitor (e.g., cyclosporine), tacrolimus, an mTOR inhibitor (e.g., sirolimus, everolimus), an IMDH inhibitor (e.g., azathioprine, leflunomide, my cophenolate).

[0307] In an embodiment, the treatment blocks transmission of a coronavirus between human subjects. In an embodiment, the treatment controls the spread of coronavirus infection in a population of human subjects.

[0308] In some embodiments, the human subject or non-human animal subject is infected with a coronavirus (e.g., betacoronavirus). In some embodiments, the human subject or non- human animal subject is at risk of being infected with a coronavirus (e.g., betacoronavirus). In some embodiments, the human subject or non-human animal subject is at risk of developing acoronavirus disease (e.g., betacoronavirus). In an embodiment, a human subject or non-human animal subject is at risk of being infected with a coronavirus or at risk of developing a coronavirus disease if the subject lives in an area (e.g., city, state, country) subject to an active coronavirus outbreak (e.g., an area where at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, or more people have been diagnosed as infected with a coronavirus). In an embodiment, a human subject or non-human animal subject is at risk of being infected with a coronavirus or developing a coronavirus disease if the subject lives in an area near (e.g., a bordering city, state, country ) a second area (e.g., city, state, country ) subject to an active coronavirus outbreak (e.g., an area near a second area where at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9. at least 10, at least 20, at least 30, at least 40, or more people have been diagnosed as infected with a coronavirus). In an embodiment, the coronavirus disease is caused by a SARS-CoV-2 infection. In an embodiment, the subject or non-human animal subject has or is at risk of developing COVID- 19.

[0309] In general, methods include selecting a subject or non-human animal subject and administering to the subject an effective amount of any one of the peptides and additional therapeutic agents described herein, and optionally repeating administration as required for the prevention or treatment of a coronavirus infection or a coronavirus disease and can be administered orally, intranasally, intravenously, intradermally, subcutaneously, intramuscularly, or topically, including skin, nasal, sinus, ocular, oropharynx, respiratory tree, and lung administration. In an embodiment, the administration is by a topical respiratory application which includes application to the nasal mucosa, sinus mucosa, oropharyngeal mucosa, or respiratory7tree, including the lungs. In an embodiment, topical application includes application to the skin or eyes. A subject can be selected for treatment based on, e.g., determining that the subject is at nsk to acquire or has a coronavirus (e.g., betacoronavirus such as SARS-CoV-2) infection.

[0310] An effective amount can be administered in one or more administrations, applications or dosages. The peptides and additional therapeutic agents disclosed herein can be administered from one or more times per day to one or more times per week, including once every7other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the risk to acquire or severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of any one of the peptides and additional therapeutic agentsdescribed herein can include a single treatment or a series of treatments. For example, effective amounts can be administered at least once.

[0311] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the treatment of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a peptide that binds to a SARS-CoV-2 spike protein for use in the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0312] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for the treatment of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a peptide that binds to a SARS- CoV-2 spike protein for use in the manufacture of a medicament for the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the manufacture of a medicament for the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0313] In an aspect, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the treatment of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein for the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is a use of an additional therapeutic agent for the treatment of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0314] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the prevention of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments.provided herein is a peptide that binds to a SARS-CoV-2 spike protein for use in the prevention of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the prevention of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0315] In an aspect, provided herein is a peptide that binds to a S ARS-CoV -2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for the prevention of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a peptide that binds to a SARS- CoV-2 spike protein for use in the manufacture of a medicament for the prevention of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the manufacture of a medicament for the prevention of a coronavirus infection in a subj ect in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0316] In an aspect, provided herein is ause of apeptidethat binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the prevention of a coronavirus infection in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein for the prevention of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is a use of an additional therapeutic agent for the prevention of a coronavirus infection in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0317] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a peptide that binds to a SARS-CoV-2 spike protein for use in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subjecthas received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0318] In an aspect, provided herein is a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a peptide that binds to a SARS- CoV-2 spike protein for use in the manufacture of a medicament for inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is an additional therapeutic agent for use in the manufacture of a medicament for inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0319] In an aspect, provided herein is ause of apeptidethat binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to a method provided herein. In some embodiments, provided herein is a use of a peptide that binds to a SARS-CoV-2 spike protein for the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent. In some embodiments, provided herein is a use of an additional therapeutic agent in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, wherein the subject has received or is receiving a therapeutically effective amount of a SARS-CoV-2 spike protein.

[0320] In an embodiment, the peptide is administered to the subject via nasal, nasopharyngeal, and / or pulmonary administration. In an embodiment, the peptide is administered to the subject via nasal administration. In an embodiment, the peptide is administered to the subject via nasopharyngeal administration. In an embodiment, the peptide is administered to the subject via pulmonary administration.

[0321] In an embodiment of the methods disclosed herein, the peptide and the additional therapeutic agent are administered to the subject at the same time. In an embodiment of the methods disclosed herein, the peptide and the additional therapeutic agent are administered to the subject at different times.EXAMPLES

[0322] The examples in this Section are offered by way of illustration and not by way of limitation.Example 1: Design and Synthesis of Stapled SARS-CoV-2 Peptides Derivatized with C- terminal PEG(n)-Thiocholesterol or PEG(n)-Cholesterol Moieties

[0323] To design peptides that could block the fusion of the coronavirus to a host cell (FIG. 1), a series of stapled peptides bearing differentially localized chemical staples and derivatized with PEG(n)-thiocholesterol or PEG(n)-cholesterol moieties at the C-termini were designed and then synthesized on resin by solid phase synthesis. The differentially localized chemical staples were located within the SARS-CoV-2 HR2 domain (i.e.. amino acids 1168-1205) of the sequence of the surface (S) glycoprotein of the severe acute respiratory syndrome coronavirus 2 (see, FIGs. 2-4), and preferably within the alpha-helical region i.e., amino acids 1179-1197; see, FIG. 9), by replacing native residues with a, a-disubstituted non-natural olefinic residues (e.g., ' X ' for S-pentenyl alanine and “8” for R-octenyl alanine installed at select i. i+ 7 positions or “X” for S-pentenyl alanine installed at each of select i, i+4 positions) and combinations thereof in the form of double staples or stitches, followed by ruthenium-catalyzed olefin metathesis (see, FIGs. 5-7). Our approach to designing, synthesizing, and identifying optimal stapled peptide constructs to target the SARS-CoV-2 fusion apparatus includes the generation of Ala scan (e.g., mutants), staple scan, and variable N- and C-terminal deletion, addition, and derivatization libraries for conjugation to PEG-thiochol esterol or PEG- cholesterol moieties (see, FIG. 8). Some preferred designs incorporate staples on the noninteracting amphiphilic face of the core SARS-CoV-2 HR2 helix (e.g., SEQ ID NO: 4) or at positions at the border of the hydrophobic interaction face with the amphiphilic face of the helix (see, FIG. 9).

[0324] Stapled SARS-CoV-2 HR2 constructs bearing C-terminal derivatization with PEG(n)-thiocholesterol or PEG(n)-cholesterol moieties were designed by replacing two naturally occurring amino acids with the non-natural (R)-2-(((9H-fluoren-9- yl)methoxy)carbonylamino)-2-methyl-dec-9-enoic acid (R8) and S-2-(4'-pentenyl) alanine (S5) amino acids at i, i+ 7 positions (i.e. flanking 7 amino acids) to generate a staple spanning two a-helical turns, or with two S5 non-natural amino acids at i, i+4 positions to generate a staple spanning one a-helical turn. Asymmetric syntheses of a, a-disubstituted amino acids were performed as previously described in detail (Schafmeister et al., J. Am. Chem. Soc., 2000; Walensky et al., Science, 2004; Bird et al. Current Protocols in Chemical Biology, 2011, each of which is incorporated by reference in its entirety).

[0325] “Staple scanning” was performed to respectively identify residues and binding surfaces critical for interaction, which dictates the design of optimized constructs and negative control mutants. The peptide N-termini were capped with acetyl or a fluorophore (e.g. FITC,rhodamine), depending upon the experimental application.

[0326] Doubly stapled peptides were generated by installing two-S5-S5, two R8-S5, or other combinations of crosslinking non-natural amino acids. Multiply stapled or stitched peptides are generated using similar principles.

[0327] To enable peptide derivatization with thiocholesterol or cholesterol on resin, carboxy-thiocholesterol or carboxy -cholesterol were synthesized according to the procedure described above (see, Methods and FIG. 10). The completed resin-bound peptide was capped with an acet l group (by use of acetic anhydride) followed by deprotection of the C-terminal side chain lysine amine by treatment with 2% hydrazine. The amine was acylated with an Fmoc-protected PEG(n) amino acid (e.g., n = 1-36; e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36) at which point the olefins were crosslinked by treating with Grubbs(I) catalyst. The Fmoc was removed from the C-terminal NH of the PEG(n) amino acid and the amine acylated with carboxy-thiocholesterol or carboxy-cholesterol. The final peptide product was obtained after peptide deprotection and cleavage, and purification by reverse phase high performance liquid chromatography / mass spectrometry (EC / MS). See the full synthetic schemas in FIG. 11A-11B. Exemplary i, i+ 7 stapled SARS-CoV-2 HR2 peptides derivatized with PEG(n)-thiocholesterol and PEG(n)-cholesterol generated by use of the synthetic schemas are listed in FIG. 12 (SEQ ID NOs: 7-21).Example 2: Identifying optimally stapled SARS-CoV-2 HR2 peptides bearing a C-terminal PEG4-thiocholesterol to achieve anti-viral activity in pseudotype and live virus assays

[0328] We first demonstrated that applying our chemical schema to append a PEG4- thiocholesterol moiety to the C-terminus of SEQ ID NO: 5 (unstapled peptide with C-terminal amide) to generate SEQ ID NO: 6 (unstapled peptide with C-terminal PEG4-thiocholesterol) transformed an inactive HR2 peptide into an active construct that demonstrated dose- responsive anti-viral activity in a pseudoviorus assay (see Methods) using Wuhan-Hu-1 pseudovirus, 293T-ACE2 cells, and peptide serial 2-fold dilution starting at 500 nM (see, FIG. 13). We then demonstrated that a stapled HR2 peptide bearing the PEG4-thiocholesterol moiety appended on-resin (Staple D, SEQ ID NO: 10) exhibited consistent and potent antiviral activity in the pseudo virus assay whether the cells were treated wi th peptide ( 1 pM) before or after viral inoculation across a series of SARS-CoV-2 pseudovirus variants, including D614G B.l, Wuhan-Hu-1, B. 1.526. B.1.427, B. l.1.7 (see. FIG. 14). In contrast, the corresponding unstapled peptide bearing the PEG4-thiocholesterol moiety (SEQ ID NO: 6)was ineffective when applied after viral inoculation and exhibited less anti-viral activity compared to the stapled sequence even when applied before viral inoculation with the same series of SARS-CoV-2 pseudovirus variants (see, FIG. 14).

[0329] We compared the unstapled (SEQ ID NO: 6) and two stapled constructs bearing i, i+ 7 staples (SEQ ID NOs: 10 and 17) on the non-interacting hydrophilic face of the HR2 helix in the pseudoviral assay (pseudovirus: B.1.526; cells: 293T-ACE2; serial dilution starting at 1 mM). The stapled HR2 peptide of SEQ ID NOTO (Staple D) showed the most potent, dose- responsive anti-viral activity followed by the unstapled peptide of SEQ ID NO: 6; notably, the stapled peptide of SEQ ID NO: 17 (Staple K) was the least active in the pseudovirus assay despite its staple also localized to the non-interacting face of the HR2 helix (see, FIG. 15). These data underscore the unpredictability of locating the optimal staple position(s). which must be determined experimentally.

[0330] To expand the analysis, we next evaluated the differential antiviral activity of a series of i, i+ 7 stapled HR2 peptides bearing a C-terminal PEG4-thiochol esterol moiety, as appended on-resin. Whereas peptides of SEQ ID NOs: 11, 14, and 15 (Staples E, H, I, respectively) showed little to no activity and peptides of SEQ ID NOs: 13 and 16 (Staples G and J, respectively) exhibited moderate activity, the peptide of SEQ ID NO: 10 (Staple D) stood out as having uniquely potent activity among the various stapled HR2 peptides in the SARS- CoV-2 pseudovirus assay (pseudovirus: D614G B. l; cells: 293T-ACE2; peptide doses of 100, 300, 1000 nM) (see, FIG. 16). We then sought to corroborate this hierarchy of peptide activity in a live SARS-CoV-2 assay. We tested the differential antiviral activity of the same series of i, i+ 7 stapled HR2 peptides bearing a C-terminal PEG4-thiocholesterol moiety. Whereas peptides of SEQ ID NOs: 11, 14, 15 (Staples E, H, I) showed little to no activity and peptides of SEQ ID NOs: 13, 16 (Staples G, J) exhibited moderate activity, the peptide of SEQ ID NO: 10 (Staple D), consistent with the pseudo virus assays results shown in FIG. 16, stood out as having uniquely potent activity among the various stapled HR2 peptides in this SARS-CoV-2 live virus assay (live virus: USA-WA1 / 2020; cells: VeroB6; peptide dose-range 8-1000 nM) (see, FIG. 17). In performing a complete i, i+7 staple scan through the alpha-helical portion of the HR2 sequence and then testing the resultant constructs in a live virus assay using the S ARS- CoV-2 Beta strain, we again found that SEQ ID NOTO (Staple D), demonstrated among the most potent antiviral activity, along with three additional staple positions (SEQ ID NOs: 13, 17, and 20 with respective staple positions G, K, and N) (FIG. 18A). The select few' constructs (SEQ ID NOs: 10. 13, 17, 20) that afford potent antiviral activity discretely colocalize to a focal region of the HR2 alpha-helical surface, as demonstrated by a helical wheel depiction(FIG. 18B). Among the SARS-CoV-2 variants tested in a pseudo viral assay, the stapled lipopeptide corresponding to SEQ ID NO: 10 (Staple D) bearing a C-terminal PEG4 thiocholesterol moiety was most active against the Omicron variant (FIG. 19), with potent antiviral activity also demonstrated against SARS-CoV-2 live viral strains, including Beta and Delta (FIG. 20). Additional constructs, corresponding to SEQ ID NOs: 13 and 20 bearing a C- terminal PEG4 thiocholesterol moiety also demonstrated consistent antiviral activity against a diversity of SARS-CoV-2 variant and SARS-CoV-1 pseudoviruses and live SARS-CoV-2 Beta strain virus (FIGs. 21-23). The tolerance for mutagenesis within the HR2 sequence, which alternatively has contacts with the HR1 core or is solvent exposed (FIG. 24A), was demonstrated for exemplary alanine substitutions in SEQ ID NO: 10 bearing a C-terminal PEG4 thiocholesterol moiety, as revealed by retention of antiviral potency in a SARS-CoV-1 pseudoviral assay (FIGs. 24B).

[0331] Taken together, these data show that (1) appending a PEG4-thiocholesterol moiety using on-resin methodology to the C-terminus of an HR2 peptide can endow potent, dose- responsive antiviral activity; (2) stapling can not only enhance peptide activity compared to the unstapled analog but also achieve antiviral activity whether administered before or after viral inoculation in culture; and (3) corroborative pseudoviral and live virus assays effectively identified a select few uniquely potent stapled HR2 peptides (SEQ ID NOs: 10, 13, 17, and 20) among a complete panel of differentially i. i+ 7 stapled peptides with lesser or no activity, underscoring that discerning the optimal staple position to achieve potent antiviral activity is unpredictable and must be determined experimentally in SARS-CoV-2 antiviral assays.Example 3: Determining the optimal PEG linker length within stapled SARS-CoV-2 HR2 peptides bearing a C-terminal PEG(n)-thiocholesterol to achieve anti-viral activity in pseudotype and live virus assays

[0332] To determine the optimal PEG-chain length to link the stapled HR2 peptide to the thiocholesterol or cholesterol moiety’, a series of PEG(n) analogs were generated according to the above-described synthetic method, where n equals 3, 4, 5, 6, 7, and 8. The antiviral activity of this series of i, i+ 7 stapled HR2 peptides bearing SEQ ID NO: 10 (Staple D) and thiocholesterol spaced by variable length PEG-linkers was examined in a pseudovirus assay across a series of five SARS-CoV-2 variants (pseudoviruses: Wuhan-Hu-1, B.1.427 / B.1.429, B. l.617.2, D614G B. l, Brazilian variant P.l; cells: 293T-ACE2; serial dilution starting at 1 |j.M). The peptide of SEQ ID NO: 10 (Staple D) bearing a PEG8 linker exhibited the most potent, dose-responsive activity in this pseudovirus assay (see, FIGs. 25A-25E).

[0333] We then sought to corroborate the hierarchy of peptide activity based on PEG(n) linker length in a live SARS-CoV-2 assay. We tested the differential antiviral activity of the same series of i, i+ 7 stapled HR2 peptides of SEQ ID NO: 10 (Staple D) bearing a PEG(n) linker of n = 3, 4, 5, 6, 7, or 8 PEG moieties and appended C-terminal thiocholesterol, as constructed on-resin, in a SARS-CoV-2 live virus assay (live virus: S. African B. 1.351; cells: VeroB6; peptide serial 2-fold dilution dose-range from 1000 to 4 nM). As for the pseudo virus assay, the construct bearing a PEG8 linker moiety exhibited the most potent, dose-responsive activity in this SARS-CoV-2 live virus assay (see, FIG. 26).

[0334] Next, we generated a series of i, i+ 7 stapled HR2 peptides of SEQ ID NO: 10 (Staple D) bearing even longer PEG(n) linkers, corresponding to n = 10, 12, 14, 16, and 20. Across SARS-CoV-2 Omicron (FIG. 27) and SARS-CoV-1 (FIG. 28) pseudoviral assays, and live SARS-CoV-2 Beta strain (FIG. 29) viral assay, the longer linker lengths were as effective, and in some cases even more effective, than the PEG8 linker length. Taken together, we find that the length of the PEG linker between the stapled HR2 peptide and the thiocholesterol derivatization can be optimized to maximize antiviral activity, as evidenced across pseudovirus and live virus assays, with PEG8 and longer PEG lengths having the best activity, and compared to the series of other constructs, PEG0 and PEG3 showing the least potent activity. The superiority of the PEG8 and longer linkers, and the inferiority' of PEG3 compared to the PEG4-8 and longer species, was unpredictable and required experimental determination in SARS-CoV-2 antiviral assays.Example 4: Specificity of the Anti-viral Mechanism of Action of stapled SARS-CoV-2 HR2 peptides bearing a C-terminal PEG(n)-thiocholesterol

[0335] To examine the specificity of the peptides of the invention for SARS-CoV-2 virus, the series of i, i+7 stapled SARS-CoV-2 HR2 peptides bearing a PEG(n)-thiocholesterol moiety of variable PEG length (n = 3-8) (Staple D, SEQ ID NO: 10) were tested in a pseudoviral assay of VSV with MLV core. Whereas the corresponding unstapled peptide demonstrated some non-specific anti-viral activity (2.5 pM dosing, 48 hours), none of the stapled HR2 constructs bearing a PEG(n)-thiocholesterol with PEG linkers of n = 3, 4, 5. 6, 7, or 8 showed any anti- VSV pseudoviral activity (see, FIG. 30).

[0336] Next, we examined whether unstapled or the stapled SARS-CoV-2 HR2 peptides of the invention bearing a PEG(n)-thiocholesterol moiety generated synthetically on-resin exhibited any cytotoxicity in the antiviral dose-effective range. Comparing peptide of the invention SEQ ID NO:6 with an alternatively synthesized unstapled HR2 construct bearing aGSGSGC linker and PEG4-cholesterol appended at the C-terminus in solution (DeVries et al, Science, 2021), we find that the unstapled HR2 peptide of SEQ ID NO:6, and generated according to our above-described on-resin method, showed comparatively enhanced antiviral activity in a live virus assay (live virus: S. African B. 1.351; cells: VeroB6; peptide dose-range 4-1000 nM) (see, FIG. 31). Further, the unstapled HR2 peptide of SEQ ID NO:6 and the corresponding i, i+7 stapled HR2 peptide of SEQ ID NO: 10 (Staple D, PEG4-thicholesterol) showed no cytotoxic activity across the anti-viral dose-effective range, as measured by DRAQ7 and Hoechst 33342 staining, whereas the unstapled HR2 peptide bearing a GSGSGC linker and C-terminally appended PEG4-cholesterol (DeVries et al, Science, 2021) killed cells within the dosing range (pseudovirus: D614G B.l; cells: 293T-ACE2; serial 2-fold dilution starting at 1 pM; read-out: 48 h) (see, FIG. 32).Example 5: SARS-CoV-25-HB Binding Activity and Broad SARS-CoV-2 Anti-viral Activity Across Variants of a stapled SARS-CoV-2 HR2 peptide bearing a C-terminal PEG8-Chol

[0337] A direct fluorescence polarization binding assay revealed low nanomolar binding affinity of a stapled lipopeptide of composition corresponding to SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol and at the N-terminus with FITC-|3-Ala in place of the acetyl, to a recombinant five-helix bundle (5-HB) of SARS-CoV-2, with the addition of the FITC- stapled lipopeptide completing the fusogenic six helix bundle (peptide: 5 nM; 5-HB protein of sequence MQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQALNTLVKQLSSGGSGGDI SGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGSSGGQKLIANQFNSAIGKIQDSLS STASALGKLQDVVNQNAQALNTLVKQLSSGGSGGDISGINASVVNIQKEIDRLNEVA KNLNESLIDLQELGSSGGQKLIANQFNSAIGKIQDSLSSTASALGKLQDVVNQNAQAL NTLVKQLSSSSGGHHHHHH (SEQ ID NO: 78) serial dilution from 1000 nM) (FIG. 33). The stapled lipopeptide of SEQ ID NO: 10 derivatized at the C-terminus with PEG8-Chol demonstrated potent antiviral activity against (a) a spectrum of SARS-CoV-2 variant pseudoviruses (293-ACE2 cells, GFP-expressing pseudo viruses, peptide (serial dilution from 1000 nM). 48 hour read-out) (FIG. 34); (b) Omicron variants (293T-ACE2 cells, GFP- expressing pseudoviruses, peptide (serial dilution from 250 nM), 48 h read-out) (FIG. 35); (c) SARS-CoV-2 beta and delta live viruses (Vero cells, peptide (serial dilution from 100 nM), 48 hour read-out) (FIG. 36); and (d) common human coronaviruses, such as the alphacoronavirus NL63 (FIG. 37).Example 6: Preparation of a Stapled SARS-CoV-2 Peptide Derivatized with a C-terminalPEG(8)-Cholesterol Moiety

[0338] The following compound was prepared based on procedures described in Example 1 above: a structurally stabilized peptide conjugate represented by the following formula:[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77).

[0339] All references (e.g., publications or patents or patent applications) cited herein are incorporated herein by reference in their entireties and for all purposes to the same extent as if each individual reference (e g., publication or patent or patent application) was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

Claims

WHAT IS CLAIMED:

1. A method of treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

2. A method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

3. A method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

4. A method of treating a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

5. A method of preventing a coronavirus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

6. A method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, wherein the subject has received or is receiving a therapeutically effective amount of an additional therapeutic agent.

7. A method of treating a coronavirus infection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

8. A method of preventing a coronavirus infection in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

9. A method of inhibiting coronavirus fusion to a host cell in a subject in need thereof, wherein the subject is receiving or has received a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein, the method comprising administering to the subject a therapeutically effective amount of an additional therapeutic agent.

10. The method of any one of claims 1-9, wherein the subject is a human, a cow, a pig, a horse, a cat, a dog, a rat, a mouse, a bat, a deer, a pangolin, a mink, a ferret, or a hamster.

11. The method of any one of claims 1-10, wherein the subject is immune competent.

12. The method of any one of claims 1-10, wherein the subject is immunodeficient.

13. The method of any one of claims 1-12, wherein the coronavirus is a betacoronavirus.

14. The method of any one of claims 1-12, wherein the coronavirus is SARS-CoV-2.

15. The method of any one of claims 1-12, wherein the coronavirus is a variant of SARS- CoV-2.

16. The method of claim 15, wherein the variant is selected from Wuhan-Hu- 1, B.1.427 / B. 1.429, B. 1.617.2, D614G B.l, Brazilian variant P.l, B. l. 1.7, B. l.351, B.1.525, B. l.526, B. 1.617.1, B. 1.617.3, R2, B. 1.621, B.l.621.1, B. l. 1.529, BA. l, BA IT. BA.2, BA.3, BA.4, or BA.5.

17. The method of claim 15, wherein the variant is selected from B. 1.351, Cluster 5, Lineage B.1.1.207, Lineage B. 1.1.7, Variant of Concern 202102 / 02, Lineage B. 1.1.317, Lineage B.1.1.318, Lineage B.1.351, Lineage B.1.429, Lineage B.1.525, Lineage P.l (also known as Lineage B. 1.1.28), Lineage B. 1.1.529, Lineage BA. 1, Lineage BA. 1.1, Lineage BA.2, Lineage BA.3, Lineage BA.4 Lineage BA 5, D614G, E484K, N501Y, S477G / N, or P681H.

18. A therapeutic combination comprising: a) a therapeutically effective amount of a peptide that binds to a SARS-CoV-2 spike protein; and b) a therapeutically effective amount of an additional therapeutic agent.

19. The method or therapeutic combination of any one of claims 1-18, wherein the additional therapeutic agent is a vaccine, an antiviral agent, a monoclonal antibody, high-titer COVID- 19 convalescent plasma, an interferon, a protease inhibitor, a kinase inhibitor, or an immunomodulator.

20. The method or therapeutic combination of any one of claims 1-19, wherein the additional therapeutic agent is an antiviral agent.

21. The method or therapeutic combination of claim 20, wherein the antiviral agent is ritonavir-boosted nirmatrelvir, remdesivir, molnupiravir, ensitrelvir fumaric acid, amantadine, rimantadine, oseltamivir, zanamivir, peramivir, acyclovir, valacyclovir, penciclovir, famciclovir, ganciclovir, foscamet, cidofovir, fomivirsen, remdesivir, lopinavir, ritonavir, molnupiravir, or nirmatrelvir.

22. The method or therapeutic combination of any one of claims 1-19, wherein the additional therapeutic agent is an immunomodulator.

23. The method of claim 22, wherein the immunomodulator is a corticosteroid, an interleukin-6 inhibitor, an interleukin- 1 inhibitor, a cytokine, erythropoietin, thrombopoietin, a lymphotoxin (e.g., a tumor necrosis factor (TNF)), a hematopoietic factor such as interleukin (IL), a colony stimulating factor (e.g., granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF)), a stem cell growth factor, oran immunomodulatory drug (IMiD / CelMoD) (e.g., lenalidomide, pomalidomide, avadomide, iberdomide, or a GSPTl degrader (e.g. CC-90009; MRT-2359)).

24. The method or therapeutic combination of any one of claims 1-19, wherein the additional therapeutic agent is a monoclonal antibody.

25. The method or therapeutic combination of claim 24. wherein the monoclonal antibody is tocilizumab, bamlanivimab, etesevimab, bebtelovimab, casirivimab, imdevimab, or sotrovimab.

26. The method or therapeutic combination of any one of claims 1-19, wherein the additional therapeutic agent is an interferon.

27. The method or therapeutic combination of claim 26, wherein the interferon is IFN-a, IFN-p, or IFN-y.

28. The method or therapeutic combination of any7one of claims 1-19, wherein the additional therapeutic agent is a kinase inhibitor.

29. The method or therapeutic combination of claim 28, wherein the kinase inhibitor is a JNK inhibitor, an AXL kinase inhibitor, an ABL kinase inhibitor, a SRC kinase inhibitor, a NAK inhibitor, an AKT inhibitor, a PI3K inhibitor, a RAK inhibitor, a MEK inhibitor, a MAPK inhibitor, or a CDK inhibitor.

30. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is at most 50 amino acids in length.

31. The method or therapeutic combination of any one of claims 1 -30, wherein the peptide is 38 amino acids in length.

32. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula (I):or a pharmaceutically acceptable salt thereof, wherein: each Ri and R2 is H or a Ci to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted; each R3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted; z is 1. 2, 3, 4. 5, 6, 7. 8, 9, or 10; and each [Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35), each [Xaa]xis EIDRLN (SEQ ID NO: 36), and each [Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37).

33. The method or therapeutic combination of claim 32. wherein Ri is an alkyl.

34. The method or therapeutic combination of claim 32, wherein Ri is a methyl group.

35. The method or therapeutic combination of any one of claims 32-34, wherein R2 is an alkyl.

36. The method or therapeutic combination of any one of claims 32-34, wherein R2 is a methyl group.

37. The method or therapeutic combination of any one of claims 32-36, wherein R3 is an alkenylene.

38. The method or therapeutic combination of any one of claims 1-34, wherein the peptide is a peptide of Formula I- A:I-A or a pharmaceutically acceptable salt thereof;Rs is alkenylene;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

39. The method or therapeutic combination of claim 38, wherein the peptide is a peptide of Formula la:or a pharmaceutically acceptable salt thereof, wherein optionally the amino group of the N- terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alky l), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

40. The method or therapeutic combination of claim 38, w herein the peptide is a peptide of the formula:or a pharmaceutically acceptable salt thereof, w herein optionally the amino group of the N- terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

41. The method or therapeutic combination of any one of claims 38-40, wherein R3 is C7- 15 alkenylene.

42. The method or therapeutic combination of any one of claims 38-40, wherein R3 is C9- 13 alkenylene.

43. The method or therapeutic combination of any one of claims 38-40, wherein R3 is Cn alkenylene.

44. The method or therapeutic combination of any one of claims 38-40, wherein R3 is - (CH2)3-7-CH=CH-(CH2)3-7-.

45. The method or therapeutic combination of any one of claims 38-40, wherein R3 is - (CH2)3-7-CH=CH-(CH2)3-4-.

46. The method or therapeutic combination of any one of claims 38-40, wherein R3 is - (CH2)6-CH=CH-(CH2)3-47. The method or therapeutic combination of any one of claims 38-46, wherein the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(C 1-4 alkyl).

48. The method or therapeutic combination of any one of claims 38-46, wherein the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH3.

49. The method or therapeutic combination of any one of claims 38-48, wherein the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH250. The method or therapeutic combination of any one of claims 1-49, wherein the peptide further comprises PEG and / or a cholesterol.

51. The method or therapeutic combination of claim 50, wherein the cholesterol is thiocholesterol.

52. The method or therapeutic combination of any one of claims 1-51, wherein the peptidefurther comprises PEG(n)-cholesterol, wherein the PEG(n)-cholesterol is conjugated to the N- terminus or C-terminus of the peptide, and wherein n is 1-36, optionally wherein n is 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36.

53. The method or therapeutic combination of any one of claims 1-51, wherein the peptide further comprises PEG(n)-thiocholesterol, wherein the PEG(n)-thiocholesterol is conjugated to the N-terminus or C-terminus of the peptide, and wherein n is 1-36. optionally wherein n 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, or 36.

54. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula II:or a pharmaceutically acceptable salt thereof, wherein:Rs is alkenylene;R4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(Rs)C(O)-(Ci.6 alkylene)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;R5 is hydrogen or C1-4 alkyl;Re is one of the following: alkyl), each of which is substituted by t occurrences of R7;R7 represents independently for each occurrence C 1-3 alky l, hydroxyl, or C1-3 alkoxyl;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and t is 0, 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replacedwith -N(H)C(O)-(C 1-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

55. The method or therapeutic combination of claim 54, wherein the peptide is a peptide ofFormula Ila:Ila or a pharmaceutically acceptable salt thereof, wherein optionally the amino group of the N- terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

56. The method or therapeutic combination of claim 54, wherein the peptide is a peptide of formula:or a pharmaceutically acceptable salt thereof, wherein optionally the ammo group of the N- terminal aspartic acid in [Xaa]« is replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(0)NH2.

57. The method or therapeutic combination of any one of claims 54-56, wherein R3 is C7- 15 alkenylene.

58. The method or therapeutic combination of any one of claims 54-56, wherein R3 is C9- 13 alkenylene.

59. The method or therapeutic combination of any one of claims 54-56, wherein R3 is Cnalkenylene.

60. The method or therapeutic combination of any one of claims 54-56, wherein R3is -(CH2)3-7-CH=CH-(CH2)3-7-.The method or therapeutic combination of any one of claims 54-56, wherein R3is -(CH2)5-7-CH— CH-(CH2)3-4-.

62. The method or therapeutic combination of any one of claims 54-56, wherein R3is -(CH2)6-CH=CH-(CH2)3-.

63. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula III:or a pharmaceutically acceptable salt thereof, wherein:R.4 is **-C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Re, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y;Rs is hydrogen or Ci-4 alkyl;Re is one of the following:is substituted by t occurrences of R7;R7 represents independently for each occurrence C 1-3 alkyl, hydroxyl, or C1-3 alkoxyl;[Xaa]w is DISGINASVVNIQ (SEQ ID NO: 35):[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]yis VAKNLNESLIDLQELGK (SEQ ID NO: 37);m is 3, 4, 5. 6, 7, 8, 9, 10, 11, 12. 13, 14, 15, or 16; p is 2, 3, 4, 5. 6, 7, or 8; z is 2, 3, 4, 5, or 6; and t is 0, 1, 2, or 3; wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(C 1-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

64. The method or therapeutic combination of claim 63, wherein the peptide is a peptide ofFormula Illa:Illa or a pharmaceutically acceptable salt thereof, wherein optionally the amino group of the N- terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(CI-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

65. The method or therapeutic combination of any one of claims 54-64, wherein R4 is **- C(O)-(C2-3 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-2 alkylene)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y.

66. The method or therapeutic combination of any one of claims 54-64, wherein R4 is **- C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)-R6, wherein ** is the point of attachment to the amino group in the side chain of the C-terminal lysine in [Xaa]y.

67. The method or therapeutic combination of any one of claims 54-66, wherein the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)-(C 1-4 alkyl).

68. The method or therapeutic combination of any one of claims 54-66, wherein the amino group of the N-terminal aspartic acid in [Xaa]wis replaced with -N(H)C(O)CH3.

69. The method or therapeutic combination of any one of claims 54-68, wherein the carboxylic acid group of the C-terminal lysine in [Xaa]yis replaced with -C(O)NH2.

70. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula IV:or a pharmaceutically acceptable salt thereof, wherein:R.4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-Rs;Rs is hydrogen or C1-4 alkyl;R6is one of the following:is substituted by t occurrences of R7;R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxyl;Rs is -C(O)-(C 1.4 alkyl);[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; p is 2, 3, 4, 5, 6, 7, or 8; z is 2, 3, 4, 5. or 6; and t is 0, 1, 2, or 3.

71. The method or therapeutic combination of claim 70, wherein the peptide is a peptide of Formula IVa:or a pharmaceutically acceptable salt thereof.

72. The method or therapeutic combination of claim 70, wherein the peptide is a peptide ofFormula IVb:or a pharmaceutically acceptable salt thereof.

73. The method or therapeutic combination of claim 70, wherein the peptide is a peptide ofor a pharmaceutically acceptable salt thereof.

74. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula V:or a pharmaceutically acceptable salt thereof, whereinR4 is -C(O)-(C2-6 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-6 alkylene)-R6;Rs is hydrogen or C1-4 alkyl;R6is one of the following:is substituted by t occurrences of R7:R7 represents independently for each occurrence C1-3 alkyl, hydroxyl, or C1-3 alkoxy 1;Rs is -C(O)-(C 1.4 alkyl);[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36);[Xaa]zis VAKNLNESL1DLQELG (SEQ ID NO: 77); m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16; and t is 0, 1, 2, or 3.

75. The method or therapeutic combination of any one of claims 70-74, wherein Rs is - C(O)CH3.

76. The method or therapeutic combination of any one of claims 70-74, wherein R4 is - C(O)-(C2-3 alkylene)-[O-CH2CH2]m-N(R5)C(O)-(Ci-2 alkylene)-R6.

77. The method or therapeutic combination of any one of claims 70-74, wherein R4 is - C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)-R6.

78. The method or therapeutic combination of any one of claims 70-77, wherein Rs is hydrogen.

79. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted by t occurrences of R7.

80. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted by t occurrences of R7.

81. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted by t occurrences of R7.

82. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted bv t occurrences of R7.

83. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted by t occurrences of R7.

84. The method or therapeutic combination of any one of claims 70-77, wherein Re issubstituted by t occurrences of R7.

85. The method or therapeutic combination of any one of claims 54-84, wherein t is 0.

86. The method or therapeutic combination of any one of claims 54-84. wherein m is 4.

87. The method or therapeutic combination of any one of claims 54-84, wherein m is 8.

88. The method or therapeutic combination of any one of claims 1-29, wherein the peptide is a peptide of Formula VI:or a pharmaceutically acceptable salt thereof, whereinR4is -C(O)-(CH2CH2)-[O-CH2CH2]8-N(H)C(O)-(CH2)-R6;[Xaa]wis DISGINASVVNIQ (SEQ ID NO: 35);[Xaa]xis EIDRLN (SEQ ID NO: 36); and[Xaa]zis VAKNLNESLIDLQELG (SEQ ID NO: 77).

89. The method of any one of claims 1-17 or 19-88. wherein the method increases viral clearance in the subject.

90. The method of any one of claims 1-17 or 19-89, wherein the method prevents new variants of SARS-CoV-2 in the subject.

91. A peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the treatment of a coronavirus infection in a subject in need thereof, according to the method of any one of the previous claims.

92. A peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for the treatment of a coronavirus infection in a subject in need thereof, according to the method of any one of the previous claims.

93. Use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the treatment of a coronavirus infection in a subject in need thereof, according to the method of any one of the previous claims.

94. A peptide that binds to a SARS-CoV -2 spike protein and an additional therapeutic agent for use in the prevention of a coronavirus infection in a subject in need thereof, according to the method of any one of the previous claims.

95. A peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for the prevention of a coronavirus infection in asubject in need thereof, according to the method of any one of the previous claims.

96. Use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the prevention of a coronavirus infection in a subject in need thereof, according to the method of any one of the previous claims.

97. A peptide that binds to a SARS-CoV -2 spike protein and an additional therapeutic agent for use in the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the method of any one of the previous claims.

98. A peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for use in the manufacture of a medicament for inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the method of any one of the previous claims.

99. Use of a peptide that binds to a SARS-CoV-2 spike protein and an additional therapeutic agent for the inhibition of a coronavirus fusion to a host cell in a subject in need thereof, according to the method of any one of the previous claims.

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