Antiviral structurally stapled herpesviridae peptides and uses thereof

Abstract

The present disclosure provides structurally stapled peptides useful for the treatment and / or prevention of a Herpesviridae infection, as well as methods of treating and / or preventing a Herpesviridae infection.

Description

Attorney Docket No.: 406693-RQW-005WO (213829) ANTIVIRAL STRUCTURALLY STAPLED HERPESVIRIDAE PEPTIDES AND USES THEREOF RELATED APPLICATIONS

[0001] This applications claims priority to and benefit of U.S. Application No. 63 / 603,426,filed November 28, 2023, the entire contents of which are hereby incorporated by reference. BACKGROUND

[0002] Herpesviridae infections are responsible for a large number of infections worldwidecausing a variety of disease indications, including oral and genital herpes, chickenpox, and shingles, among others. There is a need for new prophylaxis and treatments for Herpesviridae infections in order to effectively mitigate outbreaks.

[0003] Herpesviridae contains a surface glycoprotein protein that undergoes a conformationalchange upon engagement with the host cell, resulting in formation of a bundle that fuses the host and viral membranes together enabling the formation of a fusion pore. This fusion pore allows the viral nucleocapsid to enter the cell’s cytoplasm with subsequent release of the viral DNA and replication of the virus.

[0004] Peptide-based inhibition of viral fusion is one approach for treating and / or preventingviral infection. An antiviral peptide that inhibits fusion, Enfuvirtide (Fuzeon®), was approved by the FDA in 2003 for treating HIV infection, but biophysical and pharmacologic liabilities of peptides, including loss of bioactive shape and rapid proteolysis in vivo, have limited broader application of this approach for other viruses. SUMMARY

[0005] The present disclosure provides modified peptides that are useful for the treatmentand / or prevention of Herpesviridae infections (e.g., infection by herpes virus 1, herpes virus 2, Varicella-Zoster virus, Epstein-Barr virus, or cytomegalovirus). In some embodiments, provided peptides are crosslinked (e.g., stapled) to stabilize the helical structure of the peptide. The peptides provided herein are particularly advantageous because they may not be limited to treating or preventing a particular Herpesviridae subtype and thus can be used to treat or prevent more than one subtype of Herpesviridae (e.g., alpha, beta, and / or gamma herpes viruses). Page 1 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0006] The present disclosure encompasses the recognition that blocking a conformationalchange in a gB glycoprotein of Herpesviridae may inhibit virus fusion with a host cell and provides a new strategy for preventing and / or treating Herpesviridae infections. In some embodiments, provided therapies (e.g., modified peptides described herein) are not limited to a specific Herpesviridae subtype (e.g., inhibit one or more subtypes).

[0007] In some embodiments, the present disclosure provides modified peptides of Formula I:O O H yor a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, Xaa, x, w, and y are as defined herein.

[0008] The present disclosure also provides methods of treating and / or preventing aHerpesviridae viral infection, comprising administering to a patient in need thereof a therapeutically effective amount of a modified peptide provided herein, such as a peptide of Formula I, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIG. 1 shows the portion of Herpesviridae gB corresponding to SEQ ID NO: 1 (seecircled regions).

[0010] FIG. 2 shows a synthetic scheme of the steps for on-resin derivatization of a stapledpeptide sequence with a PEG-linked cholesterol moiety. DETAILED DESCRIPTION Compounds & Definitions

[0011] Compounds (e.g., modified peptides) of the present disclosure include those describedgenerally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated.

[0012] For purposes of this disclosure, the chemical elements are identified in accordance withthe Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Page 2 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 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., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001.

[0013] Unless otherwise stated, structures depicted herein are meant to include allstereoisomeric (e.g., enantiomeric or diastereomeric) forms of the structure, as well as all geometric or conformational isomeric forms of the structure. For example, the R and S configurations of each stereocenter are contemplated as part of the disclosure. Therefore, single stereochemical isomers, as well as enantiomeric, diastereomic, and geometric (or conformational) mixtures of provided compounds are within the scope of the disclosure. Unless otherwise stated, all tautomeric forms of provided compounds are within the scope of the disclosure.

[0014] Unless otherwise indicated, structures depicted herein are meant to include compoundsthat differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures including replacement of hydrogen by deuterium or tritium, or replacement of a carbon by13C- or14C-enriched carbon are within the scope of this disclosure.

[0015] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e.,unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “cycloaliphatic”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” refers to a monocyclic C3-C6 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. Page 3 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0016] The term “alkyl”, used alone or as part of a larger moiety, refers to a saturated,optionally substituted straight or branched hydrocarbon group having (unless otherwise specified) 1-12, 1-10, 1-8, 1-6, 1-4, 1-3, or 1-2 carbon atoms (e.g., C1-12, C1-10, C1-8, C1-6, C1 -4, C1- 3, or C1-2). Exemplary alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, and heptyl.

[0017] The term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is apolymethylene 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 herein for a substituted aliphatic group.

[0018] The term “alkenyl”, used alone or as part of a larger moiety, refers to an optionallysubstituted straight or branched hydrocarbon chain having at least one double bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkenyl groups include ethenyl, propenyl, butenyl, pentenyl, hexenyl, and heptenyl.

[0019] The term “alkenylene” refers to a bivalent alkenyl group. A substituted alkenylenechain is a bivalent hydrocarbon chain containing at least one double bond, in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.

[0020] The term “alkynyl”, used alone or as part of a larger moiety, refers to an optionallysubstituted straight or branched chain hydrocarbon group having at least one triple bond and having (unless otherwise specified) 2-12, 2-10, 2-8, 2-6, 2-4, or 2-3 carbon atoms (e.g., C2-12, C2-10, C2-8, C2-6, C2-4, or C2-3). Exemplary alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, and heptynyl.

[0021] As used herein, the term “alkynylene” refers to a bivalent alkynyl group. A substitutedalkynylene chain is a bivalent hydrocarbon chain containing at least one triple bond, in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for a substituted aliphatic group.

[0022] 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 six to fourteen 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 Page 4 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Unless otherwise specified, “aryl” groups are hydrocarbons.

[0023] As used herein, the term “bicyclic ring” or “bicyclic ring system” refers to any bicyclicring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation, having one or more atoms in common between the two rings of the ring system. Thus, the term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic” that requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions and are optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, a bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0024] The term “halogen” or “halo” means F, Cl, Br, or I.

[0025] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, orsilicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0026] 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, preferably 5, 6, or9 ring atoms; having 6, 10, or 14 ^ electrons shared in a cyclic array; and having, in addition tocarbon atoms, from one to five heteroatoms (e.g., 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur). 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. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H–quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl. A heteroaryl Page 5 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 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.

[0027] As used herein, the terms “heterocycle,” “heterocyclyl,” and “heterocyclic ring” areused interchangeably and refer to a stable 3– to 7–membered monocyclic or 5– 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–2H–pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in N–substituted pyrrolidinyl). 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, tetrahydrothienyl, piperidinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and thiamorpholinyl. A heterocyclyl group may be mono-, bi-, tri-, or polycyclic, preferably mono-, bi-, or tricyclic, more preferably mono- or bicyclic. A bicyclic heterocyclic ring also includes groups in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings. Exemplary bicyclic heterocyclic groups include indolinyl, isoindolinyl, benzodioxolyl, 1,3-dihydroisobenzofuranyl, 2,3-dihydrobenzofuranyl, and tetrahydroquinolinyl. A bicyclic heterocyclic ring can also be a spirocyclic ring system (e.g., 7- to 11-membered spirocyclic heterocyclic ring having, in addition to carbon atoms, one or more heteroatoms as defined above (e.g., one, two, three or four heteroatoms)).

[0028] As used herein, the term “partially unsaturated,” when used in reference to a ringmoiety, 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.

[0029] The term “unsaturated,” as used herein, means that a moiety has one or more units ofunsaturation.

[0030] As described herein, compounds of the present disclosure may contain “optionallysubstituted” moieties. In general, the term “substituted,” whether preceded by the term Page 6 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) “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 by this disclosure are those that result in the formation of stable orchemically feasible compounds. The term “stable,” as used herein, refers to compounds that arenot substantially altered when subjected 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.

[0031] Suitable monovalent substituents on a substitutable carbon atom of an “optionallysubstituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; – N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; – C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; –OC(O)(CH2)0–4SR°; –SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; – C(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; –C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; –S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; – P(O)(OR^)R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; –SiR^3; –(C1–4 straight or branched alkylene)O–N(R^)2; or –(C1–4 straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6 aliphatic, –CH2Ph, –O(CH2)0– 1Ph, -CH2-(5-6 membered heteroaryl ring), or a 3–6–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 aryl mono– or Page 7 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0032] Suitable monovalent substituents on R^ (or the ring formed by taking two independentoccurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, –(CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, – (CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^, –(C1–4 straight or branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4aliphatic, – CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0033] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted”group include the following: =O, =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–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0034] Suitable substituents on the aliphatic group of R* include halogen,–R^, -(haloR^), -OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0035] Suitable substituents on a substitutable nitrogen of an “optionally substituted” groupinclude –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, – Page 8 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) C(O)CH2C(O)R†, -S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is which be substituted as defined below,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 an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0036] Suitable substituents on the aliphatic group of R† are independently halogen,–R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or -NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0037] As used herein, the term "pharmaceutically acceptable salt" refers to those salts whichare, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans or other 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.

[0038] As used herein, the term “pharmaceutically acceptable carrier” refers to any of thestandard 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 wetting agents, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and / or animals without excessive toxicity, irritation, allergic response, or other problems or complication, commensurate with a reasonable benefit / risk ratio. For examples of carriers, as well as stabilizers and adjuvants, see e.g., Martin, Remington’s Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA

[1975] .

[0039] As used herein, the terms “prevent” or “prevention”, when used in connection with theoccurrence of a disease, disorder, and / or condition, refer to reducing the risk of developing the Page 9 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) disease, disorder and / or condition and / or to delaying onset of one or more characteristics or symptoms of the disease, disorder or condition.

[0040] As used herein, the terms “subject” and “patient” are used interchangeable and refer toorganisms to be treated by the methods of the present invention. Such organisms preferably include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and most preferably includes humans.

[0041] The phrase “therapeutically effective amount,” as used herein, means that amount ofan active agent which is effective for producing some desired therapeutic effect in at least a sub- population of cells in an animal and / or a sub-population of subjects at a reasonable benefit / risk ratio applicable to any medical treatment.

[0042] As used herein, the term “treat” (also “treatment” or “treating”) refers to anyadministration of a therapy that partially or completely alleviates, ameliorates, relieves, inhibits, delays onset of, reduces severity of, and / or reduces incidence of one or more symptoms, features, and / or causes of a particular disease, disorder, and / or condition. Herpesviridae Peptides

[0043] The present disclosure provides modified peptides that are useful for the treatmentand / or prevention of Herpesviridae virus infections (e.g., herpes virus 1, herpes virus 2, Varicella- Zoster virus, or cytomegalovirus infections). In some embodiments, provided peptides are crosslinked (e.g., stapled) to stabilize the helical structure of the peptide. The modified peptides provided herein are particularly advantageous because they may not be limited to treating or preventing a particular Herpesviridae subtype and thus can be used to treat or prevent more than one subtype of Herpesviridae (e.g., alpha, beta, and / or gamma herpes viruses).

[0044] In some embodiments, the present disclosure provides a modified peptide comprisingan amino acid sequence of a Herpesviridae gB protein, or a variant thereof. In some embodiments, the present disclosure provides a modified peptide comprising an amino acid sequence of a Herpesviridae gB protein, or a variant thereof, wherein at least two amino acids comprise side chains that are linked together (e.g., to form a staple).

[0045] In some embodiments, a provided modified peptide comprises an amino acid sequencethat is substantially identical to an amino acid sequence selected from Table 1. In some embodiments, a provided modified peptide comprises an amino acid sequence that is substantially Page 10 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) identical to an amino acid sequence selected from Table 1, wherein at least two amino acids of the sequence comprise side chains that are linked together (e.g., to form a staple). Table 1. TRHEIKDSGLLDYTEVQRRNQLHDLRFAD SEQ ID NO: 1 TRDELRDTGLLDYSEIQRRNQMHSLRFYD SEQ ID NO: 2[ ] n some em o men s, prov e mo e pep es compr se an amino acid sequencethat is at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98% identical to a sequence selected from Table 1, wherein at least two amino acids of the sequence comprise side chains that are linked together (e.g., to form a staple). In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 30% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 35% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 40% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 45% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 50% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 55% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 60% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 65% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 70% identical to a sequence selected from Table Page 11 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 75% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 80% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 85% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 90% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 95% identical to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise an amino acid sequence that is at least 98% identical to a sequence selected from Table 1.

[0047] In some embodiments, the present disclosure provides a modified peptide comprisingan amino acid sequence that has 0-20 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1, wherein at least two amino acids comprise side chains that are linked together (e.g., to form a staple). In some embodiments, the present disclosure provides a modified peptide comprising an amino acid sequence that has 0-10 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise 0-5 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise 0-2 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise 1-10 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise 1-5 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1. In some embodiments, provided modified peptides comprise 1-2 substitutions, insertions, and / or deletions relative to a sequence selected from Table 1.

[0048] In some embodiments, when a modified peptide comprises an amino acid sequence thathas a substitution relative to a sequence selected from Table 1, the substitution is a conservative amino acid substitution. A “conservative amino acid substitution” means that the substitution replaces one amino acid with another amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, Page 12 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine), aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine), and acidic side chains and their amides (e.g., aspartic acid, glutamic acid, asparagine, glutamine).

[0049] In some embodiments, when a modified peptide comprises an amino acid sequence thathas a substitution relative to a sequence selected from Table 1, the substitution is alanine for aspartic acid.

[0050] In some embodiments, provided modified peptides comprise an amino acid sequence:[Xaa]u-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-[Xaa]v(SEQ ID NO: 10) wherein: each Xaa is independently a natural or unnatural amino acid; u is 0-50, inclusive; v is 0-50, inclusive; Xaa1is serine, threonine, or alanine; Xaa2is glycine, asparagine, or serine; Xaa3is leucine or valine; Xaa4is leucine or phenylalanine; Xaa5is aspartic acid; and Xaa6is tyrosine or leucine.

[0051] In some embodiments, provided modified peptides comprise an amino acid sequence:[Xaa]u-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-[Xaa]v (SEQ ID NO: 11) wherein: each Xaa is independently a natural or unnatural amino acid; u is 0-50, inclusive; v is 0-50, inclusive; Xaa1is valine, isoleucine, or methionine; Xaa2is glutamine, methionine, leucine, or phenylalanine; Xaa3is arginine; Xaa4is arginine or glutamic acid; Xaa5is asparagine, phenylalanine, or tyrosine; and Page 13 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Xaa6is glutamine or asparagine.

[0052] In some embodiments, u is 0-25, inclusive. In some embodiments, u is 0-20, inclusive.In some embodiments, u is 0-15, inclusive. In some embodiments, u is 0-10, inclusive. In some embodiments, v is 0-25, inclusive. In some embodiments, v is 0-20, inclusive. In some embodiments, v is 0-15, inclusive. In some embodiments, v is 0-10, inclusive.

[0053] In some embodiments, provided modified peptides comprise at least two amino acidside chains that are linked together (e.g., to form a staple). In some embodiments, two amino acid side chains that are linked together span one to two turns of an alpha helix of the modified peptide. In some embodiments, two amino acid side chains that are linked together span one turn of an alpha helix of the modified peptide. In some embodiments, two amino acid side chains that are linked together span two turns of an alpha helix of the modified peptide.

[0054] In some embodiments, provided modified peptides comprise at least two amino acidside chains that are linked together, wherein the two amino acids are separated by (i) 3 amino acids (e.g., side chains of amino acids at positions i and i+4); or (ii) 6 amino acids (e.g., side chains of amino acids at positions i and i+7). In some embodiments, provided modified peptides comprise at least two amino acid side chains that are linked together, wherein the two amino acids are separated by 3 amino acids (e.g., side chains of amino acids at positions i and i+4). In some embodiments, provided modified peptides comprise at least two amino acid side chains that are linked together, wherein the two amino acids are separated by 6 amino acids (e.g., side chains of amino acids at positions i and i+7).

[0055] In some embodiments, the present disclosure provides a modified peptide of FormulaI’: [Xaa]w-XL1-[Xaa]x-XL2-[Xaa]y (I’) or a pharmaceutically acceptable salt thereof, wherein: each Xaa independently represents a natural or unnatural amino acid; w, x, and y are independently 0-50, inclusive; XL1and XL2are amino acids comprising side chains that are linked together; [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to Page 14 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) an amino acid sequence selected from Table 1; each of [Xaa]w and [Xaa]y independently represents an amino acid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1, optionally wherein the N-terminal amino acid in [Xaa]w and / or the C-terminal amino acid in [Xaa]y is conjugated to a moiety described herein.

[0056] In some embodiments, the present disclosure provides a modified peptide of FormulaI: O O y or aR1and R2are each independently hydrogen or an optionally substituted C1-10 aliphatic group; R3represents linked side chain groups and is an optionally substituted bivalent, C3-20hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, — C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, — N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; each R′ is independently hydrogen or optionally substituted C1-12 aliphatic; each Xaa independently represents a natural or unnatural amino acid; w and y are each independently 0-50; x is 3-10; and [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to Page 15 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) an amino acid sequence selected from Table 1; each of [Xaa]w and [Xaa]y independently represents an amino acid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1, optionally wherein the N-terminal amino acid in [Xaa]w and / or the C-terminal amino acid in [Xaa]y is conjugated to a moiety described herein.

[0057] In some embodiments, the present disclosure provides a modified peptide of FormulaI-A: or a pharmaceuticallyx, and [Xaa]y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0058] In some embodiments, the present disclosure provides a modified peptide of FormulaI-B:or a pharmaceutically acceptable salt thereof, wherein R3, [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0059] In some embodiments, the present disclosure provides a modified peptide selectedfrom: Page 16 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or

[0060] In some embodiments, the present disclosure provides a modified peptide of FormulaI-C: or a pharmaceuticallyx, and [Xaa]y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; p is 2, 3, 4, 5, 6, 7, or 8; and q is 2, 3, 4, 5, or 6.

[0061] In some embodiments, the present disclosure provides a modified peptide of FormulaI-Ci:or a pharmaceutically acceptable salt thereof, wherein [Xaa]w, [Xaa]x, and [Xaa]y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination. Page 17 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0062] In some embodiments, the present disclosure provides a modified peptide of FormulaI-Cii: or a pharmaceutically x, and [Xaa]y are as definedabove for Formula I and described in classes and subclasses herein, both singly and in combination.

[0063] As defined generally above, in Formula I’, XL1 and XL2 are amino acids comprisingside chains that are linked together. In some embodiments, XL1and XL2(e.g., two amino acids comprising side chains that are linked together) have the structure of Formula XI:wherein R1, R2, and R3are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination.

[0064] In some embodiments, XL1 and XL2 (e.g., two amino acids comprising side chains thatare linked together) have the structure of Formula XIa: wherein R3is as defined aboveclasses and subclasses herein, both singly and in combination.

[0065] In some embodiments, XL1 and XL2 (e.g., two amino acids comprising side chains thatare linked together) have the structure selected from: Page 18 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or

[0066] In some embodiments, XL1 and XL2 (e.g., two amino acids comprising side chains thatare linked together) have the structure of Formula XII: wherein p is 2, 3, 4, 5, 6, 7, or

[0067] In some embodiments, XL1 and XL2 (e.g., two amino acids comprising side chains thatare linked together) have the structure of Formula XIIa:

[0068] In someacids comprising side chains thatare linked together) have the structure of Formula XIIb: Page 19 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0069] In some acids comprising side chains thatare linked together) have the structure

[0070] In someacids comprising side chains thatare linked together) have the structure of Formula XIId:

[0071] In someherein, R1 is hydrogen or C1-10aliphatic. In some embodiments, R1is hydrogen. In some embodiments, R1is optionally substituted C1-10aliphatic (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R1is optionally substituted C1-10 alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1is optionally substituted C2-10alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In certain embodiments, R1is optionally substituted C2-10 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1is C1-10 alkyl. In some embodiments, R1is C2-10alkenyl. In some embodiments, R1is C2-10alkynyl. In some embodiments, R1is optionally substituted C1-4alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1is optionally substituted C2-4 Page 20 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R1is optionally substituted C2-4 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1is C1-4 alkyl. In some embodiments, R1is C2-4alkenyl. In some embodiments, R1is C2-4alkynyl. In some embodiments, R1is methyl.

[0072] In some embodiments of any Formulae described herein, R2 is hydrogen or C1-10aliphatic. In some embodiments, R2is hydrogen. In some embodiments, R2is optionally substituted C1-10 aliphatic (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R2is optionally substituted C1-10 alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R2is optionally substituted C2-10alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In certain embodiments, R2is optionally substituted C2-10 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R2is C1-10 alkyl. In some embodiments, R2is C2-10alkenyl. In some embodiments, R2is C2-10alkynyl. In some embodiments, R2is optionally substituted C1-4 alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R2is optionally substituted C2-4 alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R2is optionally substituted C2-4 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R2is C1-4 alkyl. In some embodiments, R2is C2-4alkenyl. In some embodiments, R2is C2-4alkynyl. In some embodiments, R2is methyl.

[0073] In some embodiments of any Formulae described herein, R1 and R2 are each hydrogen.In some embodiments, R1and R2are each independently optionally substituted C1-10 aliphatic (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R1and R2are each independently optionally substituted C1-10 alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently optionally substituted C2-10alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently optionally substituted C2-10 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently C1-10aliphatic. In some embodiments, R1and R2are each independently C1-10alkyl. In some embodiments, R1and R2are Page 21 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) each independently C2-10alkenyl. In some embodiments, R1and R2are each independently C2-10alkynyl. In some embodiments, R1and R2are each independently optionally substituted C1-4 aliphatic (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently optionally substituted C1-4alkyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently optionally substituted C2-4 alkenyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3alkoxy). In some embodiments, R1and R2are each independently optionally substituted C2-4 alkynyl (e.g., optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy). In some embodiments, R1and R2are each independently C1-4 aliphatic. In some embodiments, R1and R2are each independently C1-4alkyl. In some embodiments, R1and R2are each independently C2-4alkenyl. In some embodiments, R1and R2are each independently C2-4alkynyl. In certain embodiments, R1and R2are each methyl.

[0074] In some embodiments of any Formulae described herein, R3 is an optionally substitutedbivalent, C7-16hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)— , —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, — S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some embodiments, R3is an optionally substituted bivalent, C7-12 hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, — N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, — N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—.

[0075] In some embodiments of any Formulae described herein, R3 is an optionally substitutedbivalent, C3-20 hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O— , —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, — N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or — C(O)O—. In some embodiments, R3is an optionally substituted bivalent, C7-16hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, — C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, — S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some embodiments, R3is Page 22 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) an optionally substituted bivalent, C7-12hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, — C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—.

[0076] In some embodiments of any Formulae described herein, R3 is an optionally substitutedbivalent, C3-20hydrocarbon chain. In some embodiments, R3is an optionally substituted bivalent, C7-16 hydrocarbon chain. In some embodiments, R3is an optionally substituted bivalent, C7-12 hydrocarbon chain. In some embodiments, R3is an optionally substituted bivalent, C3-20 hydrocarbon chain comprising at least one double bond. In some embodiments, R3is an optionally substituted bivalent, C7-16hydrocarbon chain comprising at least one double bond. In some embodiments, R3is an optionally substituted bivalent, C7-12 hydrocarbon chain comprising at least one double bond.

[0077] In some embodiments of any Formulae described herein, R3 is a bivalent, C3-20hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, — C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, — S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some embodiments, R3is a bivalent, C7-16 hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, — C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, — S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some embodiments, R3is a bivalent, C7-12 hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, — C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, — S(O)2N(R′)—, —C(O)S—, or —C(O)O—.

[0078] In some embodiments of any Formulae described herein, R3 is a bivalent, C3-20hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S— , —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, — N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some Page 23 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) embodiments, R3is a bivalent, C7-16hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, — C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—. In some embodiments, R3is a bivalent, C7-12 hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, — C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)O—, — S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—.

[0079] In some embodiments of any Formulae described herein, R3 is a bivalent, C3-20hydrocarbon chain. In some embodiments, R3is a bivalent, C7-16hydrocarbon chain. In some embodiments, R3is a bivalent, C7-12 hydrocarbon chain. In some embodiments, R3is a bivalent, C3-20 hydrocarbon chain comprising at least one double bond. In some embodiments, R3is a bivalent, C7-16hydrocarbon chain comprising at least one double bond. In some embodiments, R3is a bivalent, C7-12 hydrocarbon chain comprising at least one double bond.

[0080] In some embodiments of any Formulae described herein, R3 is C7-12 alkenylene. In someembodiments, R3is C8alkenylene. In some embodiments, R3is C11alkenylene. In some embodiments, R3is -(CH2)1-7-CH=CH-(CH2)1-7-. In some embodiments, R3is -(CH2)3-7-CH=CH- (CH2)3-4-. In some embodiments, R3is -(CH2)6-CH=CH-(CH2)3-. In some embodiments, R3is - (CH2)3-CH=CH-(CH2)3-.

[0081] In some embodiments of any Formulae described herein, R3 spans one to two turns ofan alpha helix. In some embodiments, R3spans one turn of an alpha helix. In some embodiments, R3spans two turns of an alpha helix.

[0082] In some embodiments of any Formulae described herein, each R′ is independentlyhydrogen or optionally substituted C1-6 aliphatic. In some embodiments, R′ is hydrogen. In some embodiments, R′ is optionally substituted C1-12 aliphatic. In some embodiments, R′ is optionally substituted C1-6aliphatic. In some embodiments, R′ is C1-12aliphatic. In some embodiments, R′ is C1-6 aliphatic. In some embodiments, R′ is optionally substituted C1-12 alkyl. In some embodiments, R′ is optionally substituted C1-6 alkyl. In some embodiments, R′ is C1-12 alkyl. In some embodiments, R′ is C1-6alkyl. Page 24 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0083] In some embodiments of any Formulae described herein, p is 2. In some embodiments,p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8.

[0084] In some embodiments of any Formulae described herein, q is 2. In some embodiments,q is 3. In some embodiments, q is 4. In some embodiments, q is 5. In some embodiments, q is 6.

[0085] In some embodiments of any Formulae described herein, p is 5 and q is 3. In someembodiments, p is 2 and q is 3.

[0086] In some embodiments of any Formulae described herein, each Xaa is independently anatural amino acid. In some embodiments, Xaa is a natural amino acid. In some embodiments, Xaa is an unnatural amino acid. In some embodiments, 1-5 instances of Xaa are an unnatural amino acid. In some embodiments, 1-3 instances of Xaa are an unnatural amino acid. In some embodiments, one instance of Xaa is an unnatural amino acid. In some embodiments, Xaa is an N-acyl amino acid (e.g., when Xaa is at the N-terminus of a peptide). In some embodiments, Xaa is an alpha-amino amide (e.g., when Xaa is at the C-terminus of a peptide).

[0087] In some embodiments of any Formulae described herein, w is an integer from 2-50. Insome embodiments, w is an integer from 2-25. In some embodiments, w is an integer from 2-15. In some embodiments, w is an integer from 2-10. In some embodiments, w is an integer from 2-8. In some embodiments, w is an integer from 0-25. In some embodiments, w is an integer from 0- 15. In some embodiments, w is an integer from 0-10. In some embodiments, w is an integer from 0-8.

[0088] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence Page 25 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wis absent (i.e., when w is 0).

[0089] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an Page 26 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0090] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected Page 27 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0091] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising one or more contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 2 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 7 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 10 contiguous amino acids of an amino acid sequence selected from Table 1.

[0092] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 30% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 70% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 90% identical to an amino acid sequence selected from Table 1.

[0093] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 30% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 70% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 90% identical to an amino acid sequence selected from Table 1. Page 28 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0094] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1- 10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]wrepresents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-5 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-3 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0095] In some embodiments of any Formulae described herein, [Xaa]w represents an aminoacid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1- 10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1-5 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]w represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1-3 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0096] In some embodiments of any Formulae described herein, x is an integer from 3-50. Insome embodiments, x is an integer from 3-25. In some embodiments, x is an integer from 3-10. In some embodiments, x is an integer from 3-5. In some embodiments, x is an integer from 5-10. In some embodiments, x is 3 or 6. In some embodiments, x is 3. In some embodiments, x is 6.

[0097] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]xrepresents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]xrepresents an amino Page 29 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) acid sequence comprising at least 6 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0098] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 6 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0099] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 6 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. Page 30 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0100] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 6 contiguous amino acids of an amino acid sequence selected from Table 1.

[0101] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 30% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 70% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 90% identical to an amino acid sequence selected from Table 1.

[0102] In some embodiments of any Formulae described herein, [Xaa]x represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1- 10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-5 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]xrepresents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-3 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0103] In some embodiments of any Formulae described herein, y is an integer from 2-50. Insome embodiments, y is an integer from 2-25. In some embodiments, y is an integer from 2-15. In some embodiments, y is an integer from 2-10. In some embodiments, y is an integer from 2-8. In some embodiments, y is an integer from 2-5. In some embodiments, y is an integer from 0-25. In some embodiments, y is an integer from 0-15. In some embodiments, y is an integer 0-10. In some embodiments, y is an integer from 0-8. In some embodiments, y is an integer from 0-5.

[0104] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected Page 31 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y is absent (i.e., when y is 0).

[0105] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence Page 32 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 70% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0106] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 2 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino Page 33 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) acid sequence comprising at least 5 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 7 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 10 contiguous amino acids of: an amino acid sequence selected from Table 1; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from Table 1 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0107] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising one or more contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 2 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 7 contiguous amino acids of an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 10 contiguous amino acids of an amino acid sequence selected from Table 1.

[0108] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 30% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 70% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is at least 90% identical to an amino acid sequence selected from Table 1. Page 34 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0109] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 30% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 70% identical to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that is at least 90% identical to an amino acid sequence selected from Table 1.

[0110] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1- 10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-5 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that has 1-3 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0111] In some embodiments of any Formulae described herein, [Xaa]y represents an aminoacid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1- 10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]yrepresents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1-5 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, [Xaa]y represents an amino acid sequence comprising at least 5 contiguous amino acids of an amino acid sequence that has 1-3 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1.

[0112] In some embodiments of any Formulae described herein, the N-terminal amino acid in[Xaa]w is conjugated to a moiety described herein. In some embodiments, the C-terminal amino acid in [Xaa]y is conjugated to a moiety described herein. In some embodiments, the N-terminal amino acid in [Xaa]wand the C-terminal amino acid in [Xaa]yis conjugated to a moiety described herein. Page 35 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0113] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2A. Table 2A. Sequence SEQ ID NO: TRHEIKDSGLLDYTEVQRRNQLHD 12

[0114] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2B. Page 36 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2B. Sequence SEQ ID NO: TRDELRDTGLLDYSEIQRRNQMHS 36

[0115] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2C. Page 37 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2C. Sequence SEQ ID NO: SQKELRSSNVFDLEEIMREFNSYK 58

[0116] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2D. Page 38 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2D. Sequence SEQ ID NO: PDEELSRANVFDLENILREYNSYK 82

[0117] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2E. Page 39 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2E. Sequence SEQ ID NO: TKDELSKANVFDLETILREYNSYK 106

[0118] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2F. Page 40 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2F. Sequence SEQ ID NO: SRDEQRASNVFDLEGIFREYNFQA 129

[0119] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2G. Page 41 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2G. Sequence SEQ ID NO: KTVVNVASSVFDLETMFREYNYYT 152

[0120] In some embodiments of any Formulae described herein, [Xaa]w is selected from Table2H. Page 42 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 2H. Sequence SEQ ID NO: DYTEVQRRNQLHD 176

[0121] Insome embodiments of any Formulae described herein, [Xaa]x is selected from Table3A. Table 3A. Sequence SEQ ID NO: Sequence SEQ ID NO:Page 43 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: LDY 198 LDYTEV 223

[0122] In some embodiments of any Formulae described herein, [Xaa]x is selected from Table3B. Table 3B. Sequence SEQ ID NO: Sequence SEQ ID NO:Page 44 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: TGL 242 TGLLDY 261

[0123] In some embodiments of any Formulae described herein, [Xaa]x is selected from Table3C. Table 3C. Sequence SEQ ID NO: Sequence SEQ ID NO:Page 45 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: LRS 280 LRSSNV 306

[0124] In some embodiments of any Formulae described herein, [Xaa]x is selected from Table3D. Table 3D. Sequence SEQ ID NO: Sequence SEQ ID NO:Page 46 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: DEE 326 DEELSR 346

[0125] In some embodiments of any Formulae described herein, [Xaa]x is selected from Table3E. Page 47 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 3E. Sequence SEQ ID NO: Sequence SEQ ID NO: TKD 127 TKDELS 124Page 48 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0126] In some embodiments of any Formulae described herein, [Xaa]x is selected from Table3F. Table 3F. Sequence SEQ ID NO: Sequence SEQ ID NO: SRD 150 SRDEQR 147Page 49 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: IAG 408

[0127] Inlected from Table3G. Table 3G. Sequence SEQ ID NO: Sequence SEQ ID NO: KTV 173 KTVVNV 170Page 50 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Sequence SEQ ID NO: Sequence SEQ ID NO: THR 445 THRLAG 470

[0128] In, lected from Table3H. Table 3H. Sequence SEQ ID NO: Sequence SEQ ID NO:

[0129] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4A. Page 51 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4A. Sequence SEQ ID NO: KDSGLLDYTEVQRRNQLHDLRFAD 473

[0130] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4B. Page 52 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4B. Sequence SEQ ID NO: RDTGLLDYSEIQRRNQMHSLRFYD 493

[0131] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4C. Page 53 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4C. Sequence SEQ ID NO: RSSNVFDLEEIMREFNSYKQRVKY 514

[0132] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4D. Page 54 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4D. Sequence SEQ ID NO: SRANVFDLENILREYNSYKSALYT 536

[0133] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4E. Page 55 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4E. Sequence SEQ ID NO: SKANVFDLETILREYNSYKSALHH 557

[0134] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4F. Page 56 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4F. Sequence SEQ ID NO: RASNVFDLEGIFREYNFQAQNIAG 579

[0135] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4G. Page 57 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4G. Sequence SEQ ID NO: VASSVFDLETMFREYNYYTHRLAG 601

[0136] In some embodiments of any Formulae described herein, [Xaa]y is selected from Table4H. Page 58 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 4H. Sequence SEQ ID NO: QRRNQLHDLRFAD 483Page 59 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0137] In some embodiments of any Formulae described herein, [Xaa]w, [Xaa]x, and [Xaa]yare selected from Table 5A. Table 5A. [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ IDPage 60 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:

[0138] In some embodiments of any Formulae described herein, [Xaa]w, [Xaa]x, and [Xaa]yare selected from Table 5B. Table 5B. [Xaa]w[Xaa]x[Xaa]yE t XDPage 61 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:Page 62 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:

[0139] In some embodiments of any Formulae described herein, [Xaa]w, [Xaa]x, and [Xaa]yare selected from Table 5C. Table 5C. [Xaa]w[Xaa]x[Xaa]yEntry [Xaa] SEQ ID [Xaa] SEQ ID [Xaa] SEQ IDPage 63 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:Page 64 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:so e e o e s o a y o uae esc e ee , aaw, aax, a aa]yare selected from Table 5D. Table 5D. [Xaa]w[Xaa]x[Xaa]yEntry [Xaa]w SEQ ID [Xaa]x SEQ ID [Xaa]y SEQ IDPage 65 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:age o BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0141] In some embodiments of any Formulae described herein, [Xaa]w, [Xaa]x, and [Xaa]yare selected from Table 5E. Table 5E. [Xaa]w[Xaa]x[Xaa]yEntry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ IDPage 67 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:

[0142] In some embodiments of any Formulae described herein, [Xaa]w, [Xaa]x, and [Xaa]yare selected from Table 5F. Table 5F. [Xaa]w[Xaa]x[Xaa]yDPage 68 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:age o BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:

[0003] n some embodments o any ormuae descrbed eren, [ aa]w, [ aa]x, and [ aa]yare selected from Table 5G. Table 5G. [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]w SEQ ID [Xaa]x SEQ ID [Xaa]y SEQ IDPage 70 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:age o BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:y , w, x, aa]yare selected from Table 5H. Table 5H. [Xaa]w[Xaa]x[Xaa]yEntry [Xaa]wSEQ ID [Xaa]x SEQ ID [Xaa]y SEQ IDPage 72 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) [Xaa]w [Xaa]x [Xaa]y Entry [Xaa]wSEQ ID [Xaa]xSEQ ID [Xaa]ySEQ ID NO: NO: NO:

[0005] t s ou d be understood t at t e am no ac d sequences o [ aa]w, [ aa]x, and [ aa]y inTables 2A-2H, 3A-3H, 4A-4H, and 5A-5H 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 some instances, the sequences of Tables 2A-2H, 3A-3H, 4A-4H, and 5A-5H include one or more variants. In some embodiments, the amino acid sequence 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 the sequences of Tables 2A-2H, 3A-3H, 4A-4H, and 5A-5H. In some embodiments, the amino acid sequences of [Xaa]w, [Xaa]x, and [Xaa]y described herein (e.g., the sequences of Tables 2A-2H, 3A-3H, 4A-4H, and 5A-5H) may also contain one 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 the sequences of Tables 2A-2H, 3A-3H, 4A-4H, and 5A-5H), e.g., one or more (e.g., 1, 2, 3, 4, or 5) conservative and / or non-conservative amino acid substitutions.

[0146] In some embodiments of any Formulae described herein, modified peptides describedherein are at most 50 amino acids in length (i.e., w+x+y+2 ≤ 50). In some embodiments, modified peptides described herein are at most 45 amino acids in length (i.e., w+x+y+2 ≤ 45). In some Page 73 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) embodiments, modified peptides described herein are at most 30 amino acids in length (i.e., w+x+y+2 ≤ 30).

[0147] In some embodiments, modified peptides described herein comprise peptide staples.“Peptide stapling” is a term coined from a synthetic methodology wherein two amino acid side chains are covalently joined (e.g., “stapled together”). For example, two olefin-containing side- chains (e.g., cross-linkable side chains) present in a peptide chain may be 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). Peptide stapling may impart structural stabilization (see, e.g., Walensky, J. Med. Chem., 57:6275-6288 (2014)). In some cases, the staple is a hydrocarbon staple.

[0148] In some instances, 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; Orner BP, et al., J. Am. Chem. Soc.2001;123:5382; ChinJW, et al., Int. Ed. 2001;40:3806; Chapman RN, et al., J. Am. Chem. Soc. 2004;126:12252; HorneWS, 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).

[0149] In some embodiments, a stapled peptide is structurally stabilized. A peptide is“structurally stabilized” in that it maintains its native secondary structure. For example, stapling allows a peptide, predisposed to having an α-helical secondary structure, to maintain its native α- 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, modified (e.g., stapled) peptides described herein have improved biological activity and pharmacology relative to a corresponding unmodified (e.g., non-stapled (un-cross-linked)) peptides.

[0150] Non-limiting examples of non-natural amino acids that may be used as stapling aminoacids are: (R)-2-(2'-propenyl)alanine; (R)-2-(4′-pentenyl)alanine; (R)-α-(7'-octenyl)alanine; (S)-α- Page 74 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) (2′-propenyl)alanine; (S)-α-(4′-pentenyl)alanine; (S)-2-(7'-octenyl)alanine; α,α-Bis(4′- pentenyl)glycine; and α,α-Bis(7′-octeny)glycine.

[0151] In some embodiments, a staple is between two amino acids separated by, for example,6 amino acids. In some embodiments, the amino acids forming the staple are positions i and i+7. For example, where a peptide has the sequence ... X1, X2, X3, X4, X5, X6, X7, X8, X9, X10.. . , a staple can be placed between X2 and X9 or X3 and X10, etc. (i and i+7). Where a peptide has the sequence ... X1, X2, X3, X4, X5, X6, X7, X8, X9 ... , a staple can be placed between X2 and X6, X3 and X7, or X4 and X8, etc. (i and i+4). 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.

[0152] In addition, other methods of performing different types of stapling are well known inthe art and can be employed with the modified 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)). Conjugates

[0153] In some embodiments, modified peptides provided herein are conjugated to one ormore moieties. In some embodiments, a conjugated moiety is one that imparts a useful characteristic to the modified peptide, such as improved pharmacokinetic or pharmacodynamic properties (e.g., improved half-life, see, e.g., Xie, D. et al., Antimicrob. Agents Chemother. Jan. 2010, 54(1), 191-96). In some embodiments, a conjugated moiety is or comprises a lipid (e.g., cholesterol). In some embodiments, a conjugated moiety is or comprises a carbohydrate. In some embodiments, a conjugated moiety is or comprises a protein (e.g., albumin or variant thereof) or a peptide (e.g., a second modified peptide described herein). In some embodiments, a conjugated Page 75 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) moiety is attached to a modified peptide via a linker (e.g., a linker comprising polyethylene glycol (PEG)).

[0154] In some embodiments, a moiety is conjugated at or near the N-terminus of a peptide(e.g., a modified peptide described herein). For example, in some embodiments, a moiety is conjugated to the alpha-amino group of the N-terminal amino acid. In some embodiments, a moiety is conjugated at or near the C-terminus of a peptide (e.g., a modified peptide described herein). For example, in some embodiments, a lysine residue is appended to the C-terminus of a peptide and a moiety is conjugated to the lysine side chain (e.g., via the amino group). In some embodiments, a moiety is conjugated to an amino acid side chain within a peptide (e.g., a modified peptide described herein). For example, in some embodiments, a moiety is conjugated to the amino group of a lysine side chain. In some embodiments, a moiety is conjugated to an unnatural amino acid side chain within a peptide, such as an amino acid side chain comprising a maleimide or succinimide moiety.

[0155] In some embodiments, a provided modified peptide comprises: –(linker)-(lipidmoiety). In some embodiments, a linker comprises PEG, a peptide (e.g., one or more amino acids), or a combination thereof. In some embodiments, a linker comprises a peptide. In some embodiments, a linker comprises one or more PEG units. In some embodiments, a linker comprises PEG units linked by amide bonds. In some embodiments, an amino acid at the C- terminus of a provided modified peptide is conjugated to a lipid moiety via a linker group, i.e., – (linker)-(lipid moiety). In some embodiments, an amino acid at the N-terminus of a provided modified peptide is conjugated to a lipid moiety via a linker group, i.e., –(linker)-(lipid moiety).

[0156] In some embodiments, the linker comprises PEG. In some embodiments, the linker isa peptide comprising 3-20 amino acids. The linkers considered herein include those disclosed in Chen X. et al. Fusion protein linkers: property, design and functionality. Adv Drug Deliv Rev.2013 Oct;65(10):1357-69 and Zhou, J. et al. A highly potent and stable pan-coronavirus fusion inhibitor as a candidate prophylactic and therapeutic for COVID-19 and other coronavirus diseases, Acta Pharm. Sinica B; 2022;12(4): 1652-1661.

[0157] In some embodiments, a lipid moiety is C5-C100 aliphatic lipid moiety. In someembodiments, a lipid moiety is a fatty acid, phospholipid, sphingolipid, or a sterol. In some embodiments, a fatty acid is palmitic acid or stearic acid. In some embodiments, a phospholipid is phosphatidylcholine or phosphatidylethanolamine. In some embodiments, a sphingolipid is Page 76 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) sphingosine or ceramide. In some embodiments, a sterol is cholesterol, thiocholesterol, sitosterol, ergosterol, or tocopherol. In some embodiments, a lipid moiety is cholesterol.

[0158] In some embodiments, the present disclosure provides a modified peptide of FormulaII’: O O H [Xaa]xNH or a x, and [Xaa]y areas defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or - [O-CH2CH2]n, wherein n is 1-20; each R′ is independently hydrogen or optionally substituted C1-12aliphatic; and R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide).

[0159] In some embodiments, the present disclosure provides a modified peptide of FormulaII”: O O y or ax, and [Xaa]y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are Page 77 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or - [O-CH2CH2]n, wherein n is 1-20; each R′ is independently hydrogen or optionally substituted C1-12aliphatic; and R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide).

[0160] In some embodiments, the present disclosure provides a modified peptide of FormulaII: or a pharmaceuticallyand [Xaa]y are as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or - [O-CH2CH2]n, wherein n is 1-20; each R′ is independently hydrogen or optionally substituted C1-12aliphatic; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); p is 2, 3, 4, 5, 6, 7, or 8; and q is 2, 3, 4, 5, or 6.

[0161] In some embodiments, the present disclosure provides a modified peptide of FormulaIIa:Page 78 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or a pharmaceutically acceptable salt thereof, wherein [Xaa]w, [Xaa]x, and [Xaa]yare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or - [O-CH2CH2]n, wherein n is 1-20; each R′ is independently hydrogen or optionally substituted C1-12 aliphatic; and R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide).

[0162] In some embodiments, the present disclosure provides a modified peptide of FormulaIIb: or ayare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)0-6-R6; R5is hydrogen or C1-4alkyl; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); 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; and q is 2, 3, 4, 5, or 6.

[0163] In some embodiments, the present disclosure provides a modified peptide of FormulaIIc: Page 79 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or ayare as definedabove for and in combination; and R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)0-6-R6; R5is hydrogen or C1-4 alkyl; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); and m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0164] In some embodiments, the present disclosure provides a modified peptide of FormulaIVc: or ayare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)0-6-R6; R5is hydrogen or C1-4 alkyl; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); and m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0165] In some embodiments, the present disclosure provides a modified peptide of FormulaVa: Page 80 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or ayare as definedabove for in combination; and R8is -C(O)(C1-4alkyl); R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)0-6-R6; R5is hydrogen or C1-4 alkyl; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); and m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0166] In some embodiments, the present disclosure provides a modified peptide of FormulaVb:yare as defined above for Formula I and described in classes and subclasses herein, both singly and in combination; and R8is -C(O)(C1-4alkyl); R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)0-6-R6; R5is hydrogen or C1-4 alkyl; R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide); and m is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

[0167] In some embodiments of any Formulae described herein, R4 is a bivalent, straight orbranched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 Page 81 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)- , -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, - OC(O)N(R′)-, –N(R′)C(O)O-, or -[O-CH2CH2]n, wherein n is 1-20. In some embodiments, R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C6-30hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)- , -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or -[O-CH2CH2]n, wherein n is 1-20. In some embodiments, R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C3-20 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R′)S(O)2-, - S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or -[O-CH2CH2]n, wherein n is 1-20.

[0168] In some embodiments of any Formulae described herein, R4 is a bivalent, straight orbranched, saturated or unsaturated, optionally substituted C1-30hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -N(R′)C(O)-, -C(O)N(R′)- , or -[O-CH2CH2]n, wherein n is 1-20. In some embodiments, R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C6-30hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -N(R′)C(O)-, -C(O)N(R′)-, or -[O- CH2CH2]n, wherein n is 1-20. In some embodiments, R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C3-20hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -N(R′)C(O)-, -C(O)N(R′)-, or -[O- CH2CH2]n, wherein n is 1-20.

[0169] In some embodiments of any Formulae described herein, R4 is -N(H)-C(H)((CH2)4N(H)(C(O)-(C2-6alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-6alkylene)-R6))-C(O)- NH2. In some embodiments, R4is -N(H)-C(H)((CH2)4N(H)(C(O)-(C2-3 alkylene)-[O-CH2CH2]n- N(R5)C(O)-(C0-2 alkylene)-R6))-C(O)-NH2. In some embodiments, R4is -N(H)- C(H)((CH2)4N(H)(C(O)-CH2CH2-[O-CH2CH2]n-N(R5)C(O)-CH2-R6))-C(O)-NH2. In some embodiments, R4is -N(H)-C(H)((CH2)4N(H)(C(O)-(C2-3 alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0- 2 alkylene)-R6))-C(O)-NH2. In some embodiments, R4is -N(H)-C(H)((CH2)4N(H)(C(O)-CH2CH2- [O-CH2CH2]n-N(R5)C(O)-CH2-R6))-C(O)-NH2. In some embodiments, R4is -N(H)- C(H)(CH2)4N(H)(C(O)-(C2-3alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-2alkylene)-R6))-C(O)-NH2. Page 82 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) In some embodiments, R4is -N(H)-C(H)((CH2)4N(H)(C(O)-CH2CH2-[O-CH2CH2]n-N(R5)C(O)- R6))-C(O)-NH2. In some embodiments, R4is -N(H)-C(H)((CH2)4N(H)(C(O)-CH2CH2-[O- CH2CH2]n-N(R5)C(O)-R6))-C(O)-NH2.

[0170] In some embodiments of any Formulae described herein, R4 is a bivalent peptide. Insome embodiments, R4comprises an amino acid residue (e.g., lysine).

[0171] In some embodiments of any Formulae described herein, R5 is hydrogen. In someembodiments, R5is C1-4alkyl. In some embodiments, R5is methyl.

[0172] In some embodiments of any Formulae described herein, R6 is a lipid. In someembodiments, R6is a carbohydrate. In some embodiments, R6is a peptide.

[0173] In some embodiments of any Formulae described herein, R6 is an optionally substitutedC5-C100aliphatic lipid moiety. In some embodiments, R6is a fatty acid, phospholipid, sphingolipid, or a sterol. In some embodiments, R6is palmitic acid or stearic acid. In some embodiments, R6is phosphatidylcholine or phosphatidylethanolamine. In some embodiments, R6is sphingosine or ceramide. In some embodiments, R6is cholesterol, thiocholesterol, sitosterol, ergosterol, or tocopherol.

[0174] In some embodiments of any Formulae described herein, R6 is one of the following:or each ofhydroxyl or C1-3alkoxy). In some embodiments, R6is Page 83 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or

[0175] , which may be optionallysome embod6iments, R is , which may be optionally substituted (e.g., with one or more halo,C1-3 alkyl, hydroxyl or C1-3 alkoxy). In some , which may be optionally substituted (e.g., with one or3Page 84 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829), which may be optionally substituted (e.g., with one or more .R6. is InPage 85 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) is In is InPage 86 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) R6is.

[0178] .

[0179] .Page 87 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0180] In some embodiments of any Formulae described herein, -R4-R6 is:.

[0181] .

[0182] .

[0183] (CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-(CH2)-R6. In some embodiments, R9is -C(O)-(CH2CH2)-[O-CH2CH2]12- N(R5)C(O)-(CH2)-R6. In some embodiments, R9is -C(O)-(CH2CH2)-[O-CH2CH2]8-N(R5)C(O)- (CH2)-R6. In some embodiments, R9is -C(O)-(CH2CH2)-[O-CH2CH2]m-N(R5)C(O)-R6. In some embodiments, R9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(R5)C(O)-R6. In some embodiments, R9is -C(O)-(CH2CH2)-[O-CH2CH2]8-N(R5)C(O)-R6.

[0184] In some embodiments of any Formulae described herein, -R9-R6 is:.

[0185] In someis:Page 88 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) .

[0186] In.

[0187] In.

[0188] In someis:.

[0189] In.

[0190] InPage 89 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) .

[0191] In someis:.

[0192] Inis:.

[0193] In.

[0194] In8, 9, 10, 11, 12, 13,14, 15, or 16. In some embodiments, m is 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, m is 8. In some embodiments, m is 12.

[0195] In some embodiments of any Formulae described herein, n is 6, 7, 8, 9, 10, 11, 12, 13,14, 15, or 16. In some embodiments, n is 6, 7, 8, 9, 10, 11, 12, 13, or 14. In some embodiments, n is 8. In some embodiments, n is 12. Page 90 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0196] In some embodiments of any Formulae described herein, R8 is -C(O)(C1-2 alkyl). Insome embodiments, R8is -C(O)CH3.

[0197] In some embodiments, the present disclosure provides a modified peptide selected fromTable 6, or a pharmaceutically acceptable salt thereof. Table 6.R9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(H)C(O)-R6;entries from Tables 5A-5H: Entry SEQ ID SEQ ID NO Entry NOPage 91 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Entry SEQ ID Entry SEQ ID NO: NO:Page 92 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Entry SEQ ID Entry SEQ ID NO: NO:Page 93 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Entry SEQ ID Entry SEQ ID NO: NO:Page 94 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Entry SEQ ID Ent SEQ ID NO: ry NO:

[0198] In some embodiments, a provided modified peptide is a peptide conjugate furthercomprising: –(linker)-(peptide moiety). In some embodiments, a linker comprises PEG, a peptide (e.g., one or more amino acids), or a combination thereof. In some embodiments, a linker comprises a peptide. In some embodiments, a linker comprises one or more PEG units. In some embodiments, a linker comprises PEG units linked by amide bonds. In some embodiments, an amino acid at the C-terminus of a provided modified peptide is conjugated to a second peptide moiety via a linker group, i.e., –(linker)-(peptide moiety). In some embodiments, a second peptide Page 95 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) moiety is further conjugated to R6, i.e., -(linker)-(second peptide moiety)-(linker)-R6. In some embodiments, R6is a lipid moiety, e.g., a lipid moiety is one described herein. In some embodiments, R6is a protein or peptide moiety, such as albumin or a variant thereof. In some embodiments, a second peptide moiety has the same or different sequence as the modified peptide. In some embodiments, a second peptide moiety comprises a sequence of amino acids capable of binding a portion of Herpesviridae gB. In some embodiments, a second peptide moiety comprises an amino acid with an unnatural side chain comprising a moiety capable of reacting with a cysteine residue (e.g., a cysteine residue of albumin). In some embodiments, a moiety capable of reacting with a cysteine residue is a maleimide moiety.

[0199] In some embodiments, a provided modified peptide is a part of a peptide conjugate ofFormula XX: (modified peptide) – (first linker) – (second peptide moiety) – (second linker) – R6XX or a pharmaceutically acceptable salt thereof, wherein: modified peptide is a modified peptide as described herein; first linker is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, -N(R′)S(O)2-, - S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or -[O-CH2CH2]n, wherein n is 1-20; each R′ is independently hydrogen or optionally substituted C1-12aliphatic; second peptide moiety is a peptide having 10-30 amino acids; second linker is R4or R9as described herein; and R6is as described herein (e.g., a lipid moiety or a protein moiety such as albumin).

[0200] In some embodiments, a provided modified peptide is a part of a peptide conjugate ofFormula XXI:or a pharmaceutically acceptable salt thereof, wherein: modified peptide is a modified peptide as described herein; Page 96 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) second peptide moiety is a peptide having 10-30 amino acids; R4is as described herein; and R6is as described herein. Multimers

[0201] The present disclosure also provides multimeric constructs comprising more than onemodified peptide as described herein. In some embodiments, a multimeric construct comprises two modified peptides as described herein.

[0202] In some embodiments, a multimeric construct comprises Formula XXX:or a pharmaceutically acceptable salt thereof, wherein: first modified peptide and second modified peptide are each independently a modified peptide described herein; linker is a linking group; and R6is as defined herein.

[0203] In some embodiments, a first modified peptide and a second modified peptide comprisethe same amino acid sequence. In some embodiments, a first modified peptide and a second modified peptide comprise different amino acid sequences. Compositions

[0204] The present disclosure also provides compositions comprising a modified peptideprovided herein with one or more other components. In some embodiments, provided compositions comprise and / or deliver a modified peptide described herein. Page 97 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0205] In some embodiments, a provided composition is a pharmaceutical composition thatcomprises and / or delivers a modified peptide provided herein and further comprises a pharmaceutically acceptable carrier.

[0206] Provided pharmaceutical compositions may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained- release formulation; (3) topical application, for example, as a cream, ointment, or a controlled- release patch or spray applied to the skin (including to the face or genitals); (4) intravaginal or intrarectal administration, for example, as a pessary, cream or foam; (5) sublingual administration;(6) ocular administration; (7) transdermal administration; (8) nasal administration; or (9)administration via inhalation (e.g., as an aerosol or for use with a nebulizer).

[0207] In some embodiments, provided pharmaceutical compositions comprise a modifiedpeptide described herein and one or more fillers, disintegrants, lubricants, glidants, anti-adherents, and / or anti-statics, etc. Provided pharmaceutical compositions can be in a variety of forms including oral dosage forms, topical creams, topical patches, iontophoresis forms, suppository, nasal spray and / or inhaler, eye drops, intraocular injection forms, depot forms, as well as injectable and infusible solutions. Methods of preparing pharmaceutical compositions are well known in the art. Uses

[0208] In some embodiments, the present disclosure provides methods of using any of thepeptides or pharmaceutical compositions described herein for the treatment and / or prevention of a Herpesviridae virus infection. In some embodiments, provided methods are useful for treating and / or preventing oral herpes, genital herpes, chickenpox, shingles, mononucleosis, Epstein-Barr virus infection, or cytomegalovirus infection.

[0209] In some embodiments, the present disclosure provides a method of inhibiting viralfusion to a host cell in a subject in need thereof, the method comprising administering to the subject Page 98 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) a therapeutically effective amount of a peptide comprising an amino acid sequence of a Herpesviridae gB protein or a variant thereof.

[0210] In some embodiments, the present disclosure provides a method of inhibiting aconformational change in a Herpesviridae gB protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide comprising an amino acid sequence of a Herpesviridae gB protein or a variant thereof.

[0211] In some embodiments, the present disclosure provides a method of preventing and / ortreating a Herpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide comprising an amino acid sequence of a Herpesviridae gB protein or a variant thereof.

[0212] In some embodiments, the present disclosure provides a method of preventing aHerpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide comprising an amino acid sequence of a Herpesviridae gB protein or a variant thereof.

[0213] In some embodiments, the present disclosure provides a method of treating aHerpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a peptide comprising an amino acid sequence of a Herpesviridae gB protein or a variant thereof.

[0214] In some embodiments, a peptide comprising an amino acid sequence of a HerpesviridaegB protein or a variant thereof inhibits fusion of a Herpesviridae virus particle to a membrane in a host cell. In some embodiments, the peptide comprises at least 5 contiguous amino acids of an amino acid sequence selected from Table 1, or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from Table 1; and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from Table 1. In some embodiments, the peptide is any one of the peptides disclosed herein.

[0215] In some embodiments, provided herein is a method of inhibiting Herpesviridae virusparticle fusion to a host cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein. In some embodiments, the modified peptide inhibits fusion to a host cell of more than one (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten) Herpesviridae virus subtypes. In some Page 99 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) embodiments, the modified peptide inhibits fusion to a host cell of more than one Herpesviridae virus subtype (e.g., HHV1, HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8).

[0216] In some embodiments, provided herein is a method of inhibiting a conformationalchange in a Herpesviridae gB protein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein. In some embodiments, the modified peptide or a pharmaceutically acceptable salt thereof inhibits a conformational change in a Herpesviridae gB protein of more than one (e.g., two, three, four, five, six, seven, eight, or more) Herpesviridae virus subtypes. In some embodiments, the modified peptide or a pharmaceutically acceptable salt thereof inhibits a conformational change in a Herpesviridae gB protein of more than one Herpesviridae virus subtype (e.g., HHV1, HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8).

[0217] In some embodiments, provided herein is a method of preventing and / or treating aHerpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein. In some embodiments, provided herein is a method of preventing a Herpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein. In some embodiments, provided herein is a method of treating a Herpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein.

[0218] In some embodiments, provided herein is a method of preventing and / or treating aHerpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a modified peptide disclosed herein, wherein the modified peptide treats or prevents Herpesviridae virus infection caused by more than one (e.g., two, three, four, five, six, seven, eight, nine, ten, or more than ten) Herpesviridae subtype. In some embodiments, the modified peptide or a pharmaceutically acceptable salt thereof treats or prevents Herpesviridae virus infection caused by more than one Herpesviridae virus subtype (e.g., HHV1, HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8).

[0219] In some embodiments, a Herpesviridae virus is subtype HHV1, HHV2, HHV3, HHV4,HHV5, HHV6, HHV7, or HHV8. Page 100 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0220] In some embodiments, the subject has or is at risk of having a Herpesviridae virusinfection. In some embodiments, a Herpesviridae virus infection is from subtype HHV1, HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8.

[0221] In some embodiments, the subject is an animal. In some embodiments, the subject is amammal such as a non-primate (e.g., cow, pig, horse, cat, dog, rat, etc.) or a primate (e.g., monkey or human). In some embodiments, the subject is a domesticated animal (e.g., a dog or cat). In some embodiments, the subject is a human.

[0222] In some embodiments, the subject is infected with a Herpesviridae virus (e.g., HHV1,HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8). In some embodiments, the subject is at risk of being infected with a Herpesviridae virus (e.g., HHV1, HHV2, HHV3, HHV4, HHV5, HHV6, HHV7, or HHV8).

[0223] Provided modified peptides can be administered using any suitable means. In someembodiments, a peptide is administered to a subject orally, intranasally, intravenously, subcutaneously, intramuscularly, or topically, including skin, genitals, nasal, sinus, ocular, oropharynx, respiratory tree, and lung administration (e.g., via inhalation). In some embodiments, a peptide is administered by a topical respiratory application, which includes application to the nasal mucosa, sinus mucosa, oropharyngeal mucosa, or respiratory tree, including the lungs. In some embodiments, a peptide is administered by topical application to the skin, including to the face or genitals.

[0224] An effective amount of provided modified peptides can be administered in one or moreadministrations, applications or dosages. A therapeutically effective amount of a therapeutic peptide (i.e., an effective dosage) depends on the therapeutic peptide selected. Provided compositions (e.g., comprising one or more modified peptides described herein) can be administered from one or more times per day to one or more times per week. Treatment of a subject with a therapeutically effective amount of a therapeutic peptide described herein can include a single treatment or a series of treatments. For example, effective amounts can be administered at least once.

[0225] In some embodiments, provided modified peptides (including conjugates andmultimeric constructs described herein) demonstrate a particular effect in one or more assays described herein. In some embodiments, provided modified peptides demonstrate an EC50 value of less than 5 µM in the assays of Example 3. In some embodiments, provided modified peptides Page 101 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) demonstrate an EC50 value of less than 2 µM in the assays of Example 3. In some embodiments, provided modified peptides demonstrate an EC50 value of less than 1 µM in the assays of Example 3. In some embodiments, provided modified peptides demonstrate a selective index (SI) of greater than 1.5 in the assays of Example 3. In some embodiments, provided modified peptides demonstrate a SI of greater than 2 in the assays of Example 3. In some embodiments, provided modified peptides demonstrate a SI of greater than 4 in the assays of Example 3. In some embodiments, provided modified peptides demonstrate a SI of greater than 5 in the assays of Example 3. Methods of Preparing Provided Peptides

[0226] The present disclosure also provides a method of making a modified peptide disclosedherein, the method comprising: (a) providing a peptide comprising the amino acid sequence set forth in Table 1, or a variant thereof, optionally wherein the amino acid sequence comprises 2 non- naturally occurring amino acids; and (b) cross-linking the peptide, and optionally purifying the peptide.

[0227] In some embodiments, the present disclosure provides a method of synthesizing aconjugate comprising a modified peptide disclosed herein, the method comprising: (a) providing the modified peptide; and (b) derivatizing a resin bound amine of the modified peptide with a conjugated moiety on a resin. In some embodiments, a conjugated moiety is one described herein.

[0228] In some embodiments, provided herein is a method of making a peptide derivatizedwith a PEG(n)-thiocholesterol, PEG(n)-cholesterol, thiocholesterol-PEG(n), or cholesterol- PEG(n) moiety. The fully on-resin synthetic method involves (a) providing a peptide comprising at least 3 contiguous amino acids of a sequence selected from Table 1, or a variant thereof, and two non-naturally occurring amino acids, (b) cross-linking the peptide, for example, by a ruthenium catalyzed metathesis reaction, and (c) derivatizing the N-terminus and / or C-terminus on resin with a PEG linker of variable length connected to a thiocholesterol or cholesterol moiety.

[0229] In some embodiments, Fmoc-based solid-phase peptide synthesis is used to synthesizemodified peptides disclosed herein. To achieve the various staple lengths, α-methyl, α-alkenyl amino acids were installed in specific pairings at discrete positions, such as for i, i+7 positioning the use of one S-pentenyl alanine residue (S5) and one R-octenyl alanine residue (R8). For the stapling reaction, Grubbs 1st generation ruthenium catalyst dissolved in dichloroethane is added Page 102 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) to the resin-bound peptides. One or more rounds, for example three to five rounds, of stapling may be performed to ensure complete stapling. After appending the PEG(n)-thiocholesterol, PEG(n)-cholesterol, thiocholesterol-PEG(n), or cholesterol-PEG(n) moiety, the peptides are cleaved off of the resin using trifluoroacetic acid, precipitated using a hexane:ether (1:1) mixture, air dried, and purified by LC-MS.

[0230] In some embodiments, the peptides disclosed herein are made by chemical synthesismethods, which are well known to the ordinarily skilled artisan. The peptides can be synthesized using the automated Merrifield techniques of solid phase synthesis with the α-NH2 protected by either t-Boc or Fmoc chemistry using side chain protected amino acids on, for example, an Applied Biosystems Peptide Synthesizer Model 430A or 431.

[0231] In some embodiments, the peptides disclosed herein are made by solid phase peptidesynthesis (SPPS). The C-terminal amino acid is attached to a cross-linked polystyrene resin via an acid labile bond with a linker molecule. This resin is insoluble in the solvents used for synthesis, making it relatively simple and fast to wash away excess reagents and by-products. The N- terminus is protected with the Fmoc group, which is stable in acid, but removable by base. Any side chain functional groups are protected with base stable, acid labile groups.

[0232] Peptides (e.g., peptides described herein) can be made in a high-throughput,combinatorial fashion, e.g., using a high-throughput multiple channel combinatorial synthesizer available from, e.g., Advanced Chemtech or Gyros Protein Technologies. Peptide bonds can be replaced, e.g., to increase physiological stability of the peptide, by: a retro-inverso bonds (C(O)- NH); a reduced amide bond (NH-CH2); a thiomethylene bond (S-CH2or CH2-S); an oxomethylene bond (O-CH2 or CH2-O); an ethylene bond (CH2-CH2); a thioamide bond (C(S)-NH); a trans-olefin bond (CH=CH); a fluoro substituted trans-olefin bond (CF=CH); a ketomethylene bond (C(O)- CHR) or CHR-C(O) wherein R is H or CH3; and a fluoro-ketomethylene bond (C(O)-CFR or CFR- C(O)) wherein R is H or F or CH3.

[0233] The peptides disclosed herein can be further modified by: acetylation, amidation,biotinylation, cinnamoylation, farnesylation, fluoresceination, formylation, myristoylation, palmitoylation, and other lipidation, specifically including thiocholesterol or cholesterol modification using the on-resin method disclosed herein, phosphorylation (Ser, Tyr, or Thr), stearoylation, succinylation and sulfurylation. Page 103 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0234] In some embodiments, the molecules are substantially free of non-stapled peptidecontaminants or are isolated. Methods for purifying peptides include, for example, synthesizing the peptide on a solid-phase support. Following cyclization, multiple alternative solvent and purification schemes are known in the art for peptide and stapled peptide isolation and purification and may use solvents that include, but are not limited to, DMSO, DMSO / dichloromethane mixture, DMSO / NMP mixture, or a mixture / solution that does not include DMSO. The DMSO / dichloromethane or DMSO / NMP mixture may comprise about 30%, 40%, 50%, or 60% DMSO. In a specific instance, a 50% / 50% DMSO / NMP solution is used. The solution may be incubated for a period of 1, 6, 12, or 24 hours, following which the resin may be washed, for example with dichloromethane or NMP. In some embodiments, the resin is washed with NMP. Shaking and bubbling an inert gas into the solution may be performed. Assays to Characterize Stapled Peptide Conjugates

[0235] Assays to Determine α-Helicity: Compounds are dissolved in an aqueous solution(e.g.5 µM potassium phosphate solution at pH 7, or distilled H2O, to concentrations of 25-50 µM). Circular dichroism (CD) spectra are obtained on a spectropolarimeter (e.g., Jasco J-710, Aviv) using standard measurement parameters (e.g. temperature, 20 °C; wavelength, 190-260 nm; step resolution, 0.5 nm; speed, 20 nm / sec; accumulations, 10; response, 1 sec; bandwidth, 1 nm; path length, 0.1 cm). The α-helical content of each peptide is calculated by dividing the mean residue ellipticity by the reported value for a model helical decapeptide (Yang et al., Methods Enzymol., 1986).

[0236] Assays to Determine Melting Temperature (Tm): Cross-linked or the unmodifiedtemplate peptides are dissolved in distilled H2O or other buffer or solvent (e.g. at a final concentration of 50 µM) and Tm is determined by measuring the change in ellipticity over a temperature range (e.g.4 to 95 °C) on a spectropolarimeter (e.g., Jasco J-710, Aviv) using standardparameters (e.g. wavelength 222 nm; step resolution, 0.5 nm; speed, 20 nm / sec; accumulations,10; response, 1 sec; bandwidth, 1 nm; temperature increase rate: 1 °C / min; path length, 0.1 cm).

[0237] In Vitro Protease Resistance Assays: The amide bond of the peptide backbone issusceptible to hydrolysis by proteases, thereby rendering peptidic compounds vulnerable to rapid degradation in vivo. Peptide helix formation, however, typically buries and / or twists and / or shields the amide backbone and therefore may prevent or substantially retard proteolytic cleavage. The Page 104 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) peptidomimetic macrocycles of the present invention may be subjected to in vitro enzymatic proteolysis (e.g. trypsin, chymotrypsin, pepsin) to assess for any change in degradation rate compared to a corresponding uncrosslinked or alternatively stapled polypeptide. For example, the peptidomimetic macrocycle and a corresponding uncrosslinked polypeptide are incubated with trypsin agarose and the reactions quenched at various time points by centrifugation and subsequent HPLC injection to quantitate the residual substrate by ultraviolet absorption at 280 nm. Briefly, the peptidomimetic macrocycle and peptidomimetic precursor (5 mcg) are incubated with trypsin agarose (Pierce) (S / E ~125) for 0, 10, 20, 90, and 180 minutes. Reactions are quenched by tabletop centrifugation at high speed; remaining substrate in the isolated supernatant is quantified by HPLC-based peak detection at 280 nm. The proteolytic reaction displays first order kinetics and the rate constant, k, is determined from a plot of ln[S] versus time.

[0238] Peptidomimetic macrocycles and / or a corresponding uncrosslinked polypeptide can beeach incubated with fresh mouse, rat and / or human serum (e.g.1-2 mL) at 37 °C for, e.g., 0, 1, 2, 4, 8, and 24 hours. Samples of differing macrocycle concentration may be prepared by serial dilution with serum. To determine the level of intact compound, the following procedure may be used: The samples are extracted, for example, by transferring 100 µL of sera to 2 ml centrifuge tubes followed by the addition of 10 µL of 50% formic acid and 500 µL acetonitrile and centrifugation at 14,000 RPM for 10 min at 4+ / -2 °C. The supernatants are then transferred to fresh 2 ml tubes and evaporated on Turbovap under N2<10 psi, 37 °C. The samples are reconstituted in 100 µL of 50:50 acetonitrile:water and submitted to LC-MS / MS analysis. Equivalent or similar procedures for testing ex vivo stability are known and may be used to determine stability of macrocycles in serum.

[0239] Plasma Stability Assay: Stapled peptide stability can be tested in freshly drawn mouseplasma collected in lithium heparin tubes. Triplicate incubations are set up with 500 μL of plasma spiked with 10 μM of the individual peptides. Samples are gently shaken in an orbital shaker at 37 °C and 25 μL aliquots are removed at 0, 5, 15, 30, 60, 240, 360 and 480 min and added to 100 μL of a mixture containing 10% methanol:10% water:80% acetonitrile to stop further degradation of the peptides. The samples are allowed to sit on ice for the duration of the assay and then transferred to a MultiScreen Solvinert 0.45 μm low-binding hydrophilic PTFE plate (Millipore). The filtrate is directly analyzed by LC–MS / MS. The peptides are detected as double or triple charged ions Page 105 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) using a Sciex 5500 mass spectrometer. The percentage of remaining peptide is determined by the decrease in chromatographic peak area and log transformed to calculate the half-life.

[0240] In Vivo Protease Resistance Assays: Liquid chromatography / mass spectrometry-based analytical assays are used to detect and quantitate stapled peptide levels in plasma. For pharmacokinetic analysis, peptides are dissolved in sterile aqueous 5% dextrose (1 mg / mL) and administered to C57BL / 6 mice (Jackson Laboratory) by bolus tail vein or intraperitoneal injection (e.g.5, 10, 25, 50 mg / kg). Blood is collected by retro-orbital puncture at 5, 30, 60, 120, and 240 minutes after dosing 5 animals at each time point. Plasma is harvested after centrifugation (2,500 x g, 5 minutes, 4 °C) and stored at -70 °C until assayed. Peptide concentrations in plasma are determined by reversed-phase high performance liquid chromatography with electrospray ionization mass spectrometric detection (Aristoteli et al., Journal of Proteome Res., 2007; Walden et al., Analytical and Bioanalytical Chem., 2004). Study samples are assayed together with a series of 7 calibration standards of peptide in plasma at concentrations ranging from 1.0 to 50.0 µg / mL, drug-free plasma assayed with and without addition of an internal standard, and 3 quality control samples (e.g. 3.75, 15.0, and 45.0 µg / mL). Standard curves are constructed by plotting the analyte / internal standard chromatographic peak area ratio against the known drug concentration in each calibration standard. Linear least squares regression is performed with weighting in proportion to the reciprocal of the analyte concentration normalized to the number of calibration standards. Values of the slope and y-intercept of the best-fit line are used to calculate the drug concentration in study samples. Plasma concentration-time curves are analyzed by standard noncompartmental methods using WinNonlin Professional 5.0 software (Pharsight Corp., Cary, NC), yielding pharmacokinetic parameters such as initial and terminal phase plasma half-life, peak plasma levels, total plasma clearance, and apparent volume of distribution.

[0241] In vitro Binding Assays: To assess the binding and affinity of peptidomimeticmacrocycles and peptidomimetic precursors to acceptor proteins, a fluorescence polarization assay (FPA) can be used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules or peptides and then bound to proteins of high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation upon protein binding as Page 106 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) compared to fluorescent tracers attached to smaller molecules or peptides alone (e.g. FITC-labeled peptides that are free in solution).

[0242] In vitro Displacement Assays to Characterize Antagonists of Peptide-ProteinInteractions: To assess the binding and affinity of compounds that antagonize the interaction between a peptide and an acceptor protein, a fluorescence polarization assay (FPA) utilizing a fluoresceinated peptide or peptidomimetic macrocycle derived from a template peptide sequence is used, for example. The FPA technique measures the molecular orientation and mobility using polarized light and fluorescent tracer. When excited with polarized light, fluorescent tracers (e.g., FITC) attached to molecules that are then bound to proteins with high apparent molecular weights (e.g. FITC-labeled peptides bound to a large protein) emit higher levels of polarized fluorescence due to their slower rates of rotation as compared to the FITC-derivatized molecules alone (e.g. FITC-labeled peptides that are free in solution). Compounds such as unlabeled stapled peptides and their conjugates that antagonize the interaction between the fluoresceinated peptide and an acceptor protein will be detected in a competitive binding FPA experiment and the differential potency of compounds in disrupting the interaction can be quantified and compared.

[0243] Cellular Localization Assays: To measure the localization of peptides or crosslinkedpolypeptides on or in cells, intact cells are incubated with fluoresceinated crosslinked polypeptides derivatized with PEG(n)-thiocholesterol or PEG(n)-cholesterol (5 µM) for 4 hours in serum-free media or in media supplemented with human serum at 37 °C, washed twice with media and incubated with trypsin (0.25%) for 10 min at 37 °C. The cells are washed again and resuspended in PBS. Cellular fluorescence is analyzed, for example, by using either a FACSCalibur flow cytometer or Cellomics' KineticScanRTMHCS Reader. EXAMPLES

[0244] The following examples are provided to better illustrate the claimed invention and arenot to be interpreted as limiting the scope of the invention. To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention. One skilled in the art can develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention. Page 107 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Example 1. Design of Anti-Herpesviridae Stapled Peptides

[0245] The following example describes the process of designing therapeutic peptides that arebelieved to prevent a conformational change in a Herpesviridae fusion glycoprotein gB and inhibit Herpesviridae virus particle fusion with a host cell membrane. These therapeutic peptides were designed for use in several different Herpesviridae subtypes and thus could be a pan-Herpesviridae treatment and / or prophylactic.

[0246] A cascade of conformational changes of the Herpesviridae glycoproteins, including gB,mediates viral particle fusion with a host cell. (See, e.g., Lombardi, L. et al., Int. J. Biol. Macromol. 162 (2020) 882-93; Galdiero, S., et al., Journal of General Virology (2006), 87, 1085-97; and Cantisani, M., et al., J. Med. Chem.2013, 56, 8366-76). Based on these conformational changes of the Herpesviridae gB protein, a therapeutic peptide that mimics the structure of a helix within the Herpesviridae gB protein may bind to the gB protein and competitively block a conformational change, thus preventing virus particle fusion with a host cell and subsequent infection.

[0247] Initially, three portions of the HSV-1 gB protein were identified as potential candidatesfor a therapeutic peptide, as shown in Table 7. Table 7. Sequence SEQ ID NO: Based on residues in

[0248] Peptides based on the sequences in Table 7 and variants thereof were evaluated in theassay of Example 3. Based on these results, the sequence based SEQ ID NO: 1 was analyzed for its conservation across subtypes of Herpesviridae, in order to determine if this peptide sequence could be applicable to more than one Herpesviridae subtype. FIG. 1 shows the portion of gB corresponding to SEQ ID NO: 1 (see circled regions). Table 8 shows a sequence alignment of SEQ ID NO: 1 with the corresponding portion of the gB proteins in other Herpesviridae subtypes. Table 8. Subtype Sequence Alignment* SEQ ID NO:Page 108 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Subtype Sequence Alignment* SEQ ID NO: HHV-2 TRHEIKDSGLLDYTEVQRRNQLHDLRFAD 1 cid

[0249] The data in Table 8 show that the amino acids in residues 690-718 of Herpesviridae gBprotein are largely conserved between various Herpesviridae subtypes, suggesting that a therapeutic peptide designed based on these sequences may be useful in treating and / or preventing Herpesviridae infections of one or more subtypes. Example 2. Preparation of Stapled Anti-Herpesviridae Peptide Conjugates

[0250] Based on the general design of anti-Herpesviridae peptides described in Example 1,several exemplary peptide conjugates are prepared. Stapled peptide conjugates 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-octenyl alanine (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 α-helical turns, or with two S5 non-natural amino acids at i, i+4 positions to generate a staple spanning one α-helical turn. Asymmetric syntheses of α,α-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).

[0251] Briefly, a completed resin-bound peptide is capped with an acetyl group (by use ofacetic anhydride) followed by deprotection of the C-terminal side chain lysine amine by treatment with 2% hydrazine. The amine is 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 of the non-natural amino acids (e.g., S5 and S5 or R8 and S5) are crosslinked by treating with Grubbs(I) catalyst. The Fmoc is Page 109 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) removed from the C-terminal NH of the PEG(n) amino acid and the amine acylated with carboxy- cholesterol (prepared as described below). The final peptide product is obtained after peptide deprotection and cleavage, and purification by reverse phase high performance liquid chromatography / mass spectrometry (LC / MS). See the full synthetic scheme in FIG.2.

[0252] Carboxy-cholesterol is prepared according to the following scheme:

[0253] and carbondioxide gas is used. In an oven-dried 3 neck‐flask fitted with appropriate septum, reflux condenser and dropping funnel under an atmosphere of dry argon is placed magnesium turnings (1.95 g, 0.080 mole) in dry anhydrous THF (450 mL). Ethyl bromide (1.81 g, 0.016 mole) is added dropwise (20 min) via a syringe and the mixture is allowed to stir while being slowly heated. Cholesteryl chloride (25 g, 0.061 mole) in anhydrous THF (350 mL) is then added dropwise via the dropping funnel while maintaining the temperature at gentle reflux. The mixture is then allowed to stir at gentle reflux. The reaction mixture is then cooled to RT and dry carbon dioxide is gently bubbled. The mixture is then poured into ice cold solution of 10 % sulfuric acid (500 mL). The mixture is then extracted with EtOAc (750 mL x 3) and the combined EtOAc extracts are dried on sodium sulfate, filtered and EtOAc distilled off under reduced pressure. The crude residue obtained is triturated with benzene (150 ml x 2) and collected by filtration to give white solid (7.1 g). The solid is air dried under vacuum. Example 3. In Vitro Evaluation of Peptide Conjugates Against HSV-1 in Vero 76 Cells Page 110 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829)

[0254] Compounds (e.g., peptides and modified peptides described herein) were tested for invitro antiviral activity against HSV-1 in Vero 76 cells. Test media was minimum essential medium (MEM) supplemented with 2% FBS and 50 µg / mL gentamicin. Cell plates were prepared the day before treatment and infection, seeding cells at 3e4 per well in 96-well plates, and incubating overnight at 37±2 °C, 5% CO2.

[0255] Compounds were received as 10 mM solutions. Compounds were serially diluted usingeight 2-fold dilutions in test media so that the starting (high) test concentration was 10 µ^^^Each dilution was added to 5 wells of a 96-well plate containing cells. Three wells of each concentration were infected with virus, and two wells remained uninfected as toxicity controls. Six wells were infected and untreated as virus controls, and six wells were uninfected and untreated as cell controls. Virus was prepared to achieve a MOI of 0.01. Acyclovir was tested in parallel as a positive control. Plates were incubated at 37±2 °C, 5% CO2.

[0256] On day 3 post-infection, once untreated virus control wells reached maximum CPE,plates were stained with neutral red dye for approximately 2 hours (±15 minutes). Supernatant dye was removed and wells rinsed with PBS. The incorporated dye was extracted in 50:50 Sorensen citrate buffer / ethanol for >30 minutes and the optical density was read on a spectrophotometer at 540 nm. Optical densities were converted to percent of cell controls and normalized to the virus control, then the concentration of test compound required to inhibit CPE by 50% (EC50) was calculated by regression analysis. The concentration of compound that would cause 50% cell death in the absence of virus was similarly calculated (CC50). The selective index (SI) is the CC50 divided by EC50.

[0257] For the assay of this Example, the compounds in Table 9 and Table 10 were tested:Table 9. , wherein:R9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(H)C(O)-R6; and Page 111 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) SEQ ID NO:1 FARLQFTYNHIQRHVRDMEGR 977ab e 0.R9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(H)C(O)-R6; andy SEQ ID NO:

[0258] The results of this analysis are summarized in Table 11.Page 112 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) Table 11. Compound EC50 CC50 SI 1 4.3 µM 7.1 µM 1.7

[0259] While we have described a number of embodiments of this invention, it is apparent thatour basic examples may be altered to provide other embodiments that utilize the peptides and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example. Page 113 of 134 BUSINESS.32307266.1

Claims

Attorney Docket No.: 406693-RQW-005WO (213829) CLAIMS 1. A modified peptide comprising an amino acid sequence that is at least 30% identical to an amino acid sequence selected from the group consisting of: TRHEIKDSGLLDYTEVQRRNQLHDLRFAD SEQ ID NO: 1 TRDELRDTGLLDYSEIQRRNQMHSLRFYD SEQ ID NO: 2 d together (e.g., toform a staple).

2. A modified peptide comprising an amino acid sequence that has 0-10 substitutions, insertions, and / or deletions relative to SEQ ID NO: 1-9, wherein at least two amino acids comprise side chains that are linked together (e.g., to form a staple).

3. The modified peptide of claim 1 or 2, wherein the side chains that are linked together are side chains of two amino acids separated by: (i) 3 amino acids (e.g., side chains of amino acids at positions i and i+4); or (ii) 6 amino acids (e.g., side chains of amino acids at positions i and i+7).

4. The modified peptide of claim 3, wherein the side chains that are linked together are side chains of two amino acids separated by 3 amino acids (e.g., side chains of amino acids at positions i and i+4).

5. The modified peptide of claim 3, wherein the side chains that are linked together are side chains of two amino acids separated by 6 amino acids (e.g., side chains of amino acids at positions i and i+7). Page 114 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 6. The modified peptide of any one of the preceding claims, wherein the amino acid sequence is at least 70% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-9.

7. The modified peptide of any one of the preceding claims, wherein the amino acid sequence is at least 80% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-9.

8. The modified peptide of any one of the preceding claims, wherein the amino acid sequence is at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-9.

9. The modified peptide of any one of the preceding claims, wherein the amino acid sequence is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-9.

10. The modified peptide of any one of the preceding claims, wherein the amino acid sequence is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NO: 1-9.

11. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

1.

12. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

2.

13. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

3. Page 115 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 14. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

4.

15. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

5.

16. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

6.

17. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

7.

18. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

8.

19. The modified peptide of any one of claims 1-10, wherein the amino acid sequence is SEQ ID NO:

9.

20. The modified peptide of any one of the preceding claims, wherein the modified peptide is conjugated to a lipid, carbohydrate, or peptide moiety.

21. The modified peptide of claim 20, wherein the modified peptide is conjugated to a lipid, carbohydrate, or peptide moiety via a PEG moiety.

22. The modified peptide of claim 21, wherein the PEG moiety is attached at or near the C- terminus of the amino acid sequence.

23. The modified peptide of claim 21, wherein the PEG moiety is attached at or near the N- terminus of the amino acid sequence. Page 116 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 24. The modified peptide of any one of claims 20-23, wherein the modified peptide further comprises an optionally substituted C5-C100 aliphatic lipid moiety.

25. The modified peptide of claim 24, wherein the lipid moiety is a fatty acid, phospholipid, sphingolipid, or a sterol.

26. The modified peptide of claim 24 or 25, wherein the lipid moiety is cholesterol, thiocholesterol, sitosterol, ergosterol, or tocopherol.

27. The modified peptide of claim 26, wherein the lipid moiety is cholesterol.

28. A modified peptide, wherein the modified peptide is of Formula I’: [Xaa]w-XL1-[Xaa]x-XL2-[Xaa]y (I’) or a pharmaceutically acceptable salt thereof, wherein: each Xaa independently represents a natural or unnatural amino acid; w, x, and y are independently 0-50, inclusive; XL1and XL2are amino acids comprising side chains that are linked together; [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from SEQ ID NO: 1-9; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9; and each of [Xaa]w and [Xaa]y independently represents an amino acid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from SEQ ID NO: 1-9; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9, optionally wherein the N-terminal amino acid in [Xaa]w and / or the C-terminal amino acid in [Xaa]yis conjugated to a lipid, carbohydrate, or peptide moiety. Page 117 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 29. A modified peptide, wherein the modified peptide is of Formula I: O O y or aR1and R2are or an 10 aliphatic group; R3represents linked side chain groups and is an optionally substituted bivalent, C3-20hydrocarbon chain, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O—, —S—, —S—S—, —N(R′)—, — C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, — N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—; each R′ is independently hydrogen or optionally substituted C1-12 aliphatic; each Xaa independently represents a natural or unnatural amino acid; w and y are each independently 0-50; x is 3-10; and [Xaa]x represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from SEQ ID NO: 1-9; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9; each of [Xaa]wand [Xaa]yindependently represents an amino acid sequence comprising one or more contiguous amino acids of: an amino acid sequence selected from SEQ ID NO: 1-9; or an amino acid sequence that is (i) at least 30% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9, optionally wherein the N-terminal amino acid in [Xaa]wand / or the C-terminal amino acid in [Xaa]yis conjugated to a lipid, carbohydrate, or peptide moiety. Page 118 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 30. The modified peptide of claim 28 or 29, wherein each of [Xaa]w, [Xaa]x, and [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of: an amino acid sequence selected from SEQ ID NO: 1-9; or an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9, optionally wherein the N-terminal amino acid in [Xaa]w and / or the C-terminal amino acid in [Xaa]y is conjugated to a lipid, carbohydrate, or peptide moiety.

31. The modified peptide of any one of claims 28-30, wherein each of [Xaa]w, [Xaa]x, and [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence selected from SEQ ID NO: 1-9.

32. The modified peptide of any one of claims 28-30, wherein each of [Xaa]w, [Xaa]x, and [Xaa]y represents an amino acid sequence comprising at least 3 contiguous amino acids of an amino acid sequence that is (i) at least 90% identical to an amino acid sequence selected from SEQ ID NO: 1-9 and / or (ii) has 1-10 substitutions, insertions, and / or deletions relative to an amino acid sequence selected from SEQ ID NO: 1-9.

33. The modified peptide of any one of claims 28-32, wherein the C-terminal amino acid in [Xaa]y is conjugated to a lipid, carbohydrate, or peptide moiety.

34. The modified peptide of any one of claims 28-33, wherein the N-terminal amino acid in [Xaa]w is conjugated to a lipid, carbohydrate, or peptide moiety.

35. The modified peptide of any one of claims 28-34, wherein w is 7.

36. The modified peptide of any one of claims 28-35, wherein x is 6.

37. The modified peptide of any one of claims 28-36, wherein y is 0-5. Page 119 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 38. The modified peptide of any one of claims 28-37, wherein [Xaa]w is selected from Tables 2A-2H.

39. The modified peptide of any one of claims 28-38, wherein [Xaa]x is selected from Tables 3A-3H.

40. The modified peptide of any one of claims 28-39, wherein [Xaa]y is selected from Tables 4A-4H.

41. The modified peptide of any one of claims 28-40, wherein [Xaa]w, [Xaa]x, and [Xaa]yare selected from Tables 5A-5H.

42. The modified peptide of any one of claims 1-41, wherein the modified peptide is at most 50 amino acids in length (i.e., w+x+y+2 ≤ 50).

43. The modified peptide of any one of claims 1-42, wherein the modified peptide is at most 30 amino acids in length (i.e., w+x+y+2 ≤ 30).

44. The modified peptide of any one of claims 29-43, wherein R1and R2are each independently hydrogen or C1-10aliphatic optionally substituted with one or more halo, hydroxyl, or C1-3 alkoxy.

45. The modified peptide of any one of claims 29-44, wherein R1is C1-10alkyl.

46. The modified peptide of any one of claims 29-45, wherein R1is methyl.

47. The modified peptide of any one of claims 29-46, wherein R2is C1-10 alkyl.

48. The modified peptide of any one of claims 29-47, wherein R2is methyl. Page 120 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 49. The modified peptide of any one of claims 29-48, wherein the modified peptide is of Formula I-B:or a pharmaceutically acceptable salt thereof.

50. The modified peptide of any one of claims 29-48, wherein the modified peptide is selected from: or51. The modified peptide of any one of claims 29-50, wherein R3is an optionally substituted bivalent, C3-20 hydrocarbon chain comprising at least one double bond, wherein one or more methylene units of the hydrocarbon chain are optionally and independently replaced with —O— , —S—, —S—S—, —N(R′)—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, — N(R′)C(O)N(R′)—, —N(R′)C(O)O—, —S(O)—, —S(O)2—, —S(O)2N(R′)—, —C(O)S—, or —C(O)O—.

52. The modified peptide of any one of claims 29-51, wherein R3is an optionally substituted bivalent, C3-20hydrocarbon chain. Page 121 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 53. The modified peptide of any one of claims 29-52, wherein R3is C7-12 alkenylene.

54. The modified peptide of any one of claims 29-53, wherein R3is C8alkenylene.

55. The modified peptide of any one of claims 29-53, wherein R3is C11 alkenylene.

56. The modified peptide of any one of claims 29-52, wherein R3is -(CH2)1-7-CH=CH- (CH2)1-7-.

57. The modified peptide of any one of claims 29-52, wherein R3is -(CH2)3-7-CH=CH- (CH2)3-4-.

58. The modified peptide of any one of claims 29-53, wherein R3is -(CH2)6-CH=CH- (CH2)3-.

59. The modified peptide of any one of claims 29-53, wherein R3is -(CH2)3-CH=CH- (CH2)3-.

60. The modified peptide of any one of claims 29-59, wherein the modified peptide is of Formula II’: O O or aR4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -O-, -N(R′)-, -S-, -OC(O)-, -C(O)O-, -C(O)-, -S(O)-, -S(O)2-, - Page 122 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) N(R′)S(O)2-, -S(O)2N(R′)-, -N(R′)C(O)-, -C(O)N(R′)-, -OC(O)N(R′)-, –N(R′)C(O)O-, or -[O-CH2CH2]n, wherein n is 1-20; and R6is a conjugated moiety (e.g., a lipid, carbohydrate, or peptide).

61. The modified peptide of claim 60, wherein R4is a bivalent, straight or branched, saturated or unsaturated, optionally substituted C1-30 hydrocarbon chain, wherein 1-10 methylene units of the hydrocarbon chain are independently replaced by -N(R′)C(O)-, -C(O)N(R′)-, or -[O- CH2CH2]n, wherein n is 1-20.

62. The modified peptide of claim 60 or 61, wherein R6is a lipid moiety.

63. The modified peptide of any one of claims 60-62, wherein: R4is -N(H)-C(H)((CH2)4N(H)(C(O)-(C2-6 alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-6 alkylene)-R6))-C(O)-NH2; R5 is hydrogen or C1-4 alkyl;R6is an optionally substituted C5-C100 aliphatic lipid moiety; and n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

64. The modified peptide of claim 63, wherein R6is selected from: orPage 123 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) , each of which may be optionally substituted.

65. The modified peptide of claim 63 or 64, wherein R6is optionally substituted with one or more halo, C1-3alkyl, hydroxyl, or C1-3alkoxy.

66. The modified peptide of any one of claims 60-65, wherein the modified peptide is of Formula IIa1: or a pharmaceuticallyR4is -N(H)-C(H)((CH2)4N(H)(C(O)-(C2-6alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-6alkylene)- R6))-C(O)-NH2;R5 is hydrogen or C1-4 alkyl;R6is one of the following: orPage 124 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) , each of which is optionally substituted with one or more hydroxyl, or C1-3 alkoxyl;n 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; and q is 2, 3, 4, 5, or 6.

67. The modified peptide of claim 66, wherein the modified peptide is of Formula IIa: or a pharmaceutically68. The modified peptide of claim 66, wherein the modified peptide is of Formula IIIa: or a pharmaceutically69. The modified peptide of any one of claims 60-68, wherein R4is -N(H)- C(H)((CH2)4N(H)(C(O)-(C2-3 alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-2 alkylene)-R6))-C(O)- NH2.

70. The modified peptide of any one of claims 60-68, wherein R4is -N(H)- C(H)((CH2)4N(H)(C(O)-CH2CH2-[O-CH2CH2]n-N(R5)C(O)-R6))-C(O)-NH2. Page 125 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 71. The modified peptide of any one of claims 60-68, wherein -R4-R6is .

72. The modified peptide of any one of claims 60-68, wherein -R4-R6is .

73. The modified peptide of any one of claims 60-72, wherein the modified peptide is of Formula IIb: or a[O-CH2CH2]n- N(R5)C(O)-R6.

74. The modified peptide of claim 73, wherein the modified peptide is of Formula IIc:Page 126 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or a pharmaceutically acceptable salt thereof, wherein R9is -C(O)-(CH2CH2)-[O-CH2CH2]n- N(R5)C(O)-R6.

75. The modified peptide of claim 73, wherein the modified peptide is of Formula IIIc: or a -[O-CH2CH2]n-N(R5)C(O)-R6.

76. The modified peptide of any one of claims 60-74, wherein the modified peptide is of Formula V: 3n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16. Page 127 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 77. The modified peptide of any one of claims 60-73 or 75, wherein the modified peptide is of Formula Va: whereinR9is -C(O)-(C2-6 alkylene)-[O-CH2CH2]n-N(R5)C(O)-(C0-6 alkylene)-R6;R5 is hydrogen or C1-4 alkyl;R6is (C3-15alkyl) , which is optionally substituted one or more halo, C1-3 alkyl,R8is -C(O)-(C1-4alkyl); and n is 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16.

78. The modified peptide of any one of claims 60-77, wherein R6is , substituted with one or more halo, C1-3alkyl, hydroxyl, or C1-3Page 128 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 79. The modified peptide of any one of claims 60-77, wherein R6is is81. The modified peptide of any one of claims 76-80, wherein R8is -C(O)CH3.

82. The modified peptide of any one of claims 63-81, wherein R5 is hydrogen.

83. The modified peptide of any one of claims 60-82, wherein n is 4.

84. The modified peptide of any one of claims 60-82, wherein n is 8.

85. The modified peptide of any one of claims 60-82, wherein n is 12.

86. The modified peptide of any one of claims 76 or 78-85, wherein the modified peptide is of Formula VI: Page 129 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) or aR9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(H)C(O)- and .

87. The modified peptide of any one of claims 77-85, wherein the modified peptide is of Formula VII: or aR9is -C(O)-(CH2CH2)-[O-CH2CH2]12-N(H)C(O)-R6; andPage 130 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 88. A modified peptide selected from Table 6, or a pharmaceutically acceptable salt thereof.

89. The modified peptide of any one of the preceding claims, wherein the peptide is structurally stabilized.

90. The modified peptide of any one of the preceding claims, wherein two amino acid side chains are linked together to form a staple that spans one to two turns of an alpha helix of the modified peptide.

91. A pharmaceutical composition comprising the modified peptide, or pharmaceutically acceptable salt thereof, of any one of claims 1-90, and a pharmaceutically acceptable carrier.

92. A method of treating or preventing a Herpesviridae virus infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the modified peptide, or a pharmaceutically acceptable salt thereof, of any one of claims 1-90 or the pharmaceutical composition of claim 91.

93. A method of inhibiting Herpesviridae virus particle fusion to a host cell in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the modified peptide of any one of claims 1-90, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 91.

94. A method of inhibiting a conformational change in a Herpesviridae glycoprotein B (gB) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the modified peptide of any one of claims 1-90, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 91.

95. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-1 virus. Page 131 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 96. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-2 virus.

97. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-3 virus.

98. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-4 virus.

99. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-5 virus.

100. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-6 virus.

101. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-7 virus.

102. The method of any one of claims 92-94, wherein the Herpesviridae virus is a HHV-8 virus.

103. The method of any one of claims 92 or 95-102, wherein the modified peptide or a pharmaceutically acceptable salt thereof treats or prevents Herpesviridae infection caused by more than one (e.g., two, three, four, five, six, seven, or eight) Herpesviridae subtypes.

104. The method of any one of claims 93 or 95-102, wherein the modified peptide or a pharmaceutically acceptable salt thereof inhibits fusion to a host cell of more than one (e.g., two, three, four, five, six, seven, or eight) Herpesviridae subtypes. Page 132 of 134 BUSINESS.32307266.1Attorney Docket No.: 406693-RQW-005WO (213829) 105. The method of any one of claims 94-102, wherein the modified peptide or a pharmaceutically acceptable salt thereof inhibits a conformational change in a Herpesviridae gB protein of more than one (e.g., two, three, four, five, six, seven, or eight) Herpesviridae subtypes. Page 133 of 134 BUSINESS.32307266.1

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