US 2025/0288658 A1 · EBOLAVIRUS SURFACE GLYCOPROTEIN PEPTIDES, CONJUGATES, AND USES THEREOF

Abstract

This disclosure relates to structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) Ebolavirus peptides and variants thereof, and structurally-stabilized (e.g., stapled, e.g., hydrocarbon stapled) Ebolavirus peptides and variants thereof, conjugated with polyethylene glycol (PEG) and/or cholesterol (or a variant thereof, e.g., thiocholesterol), e.g., a generated PEG(n)-cholesterol or PEG(n)-thiocholesterol derivatization to further optimize activity, and methods for using such structurally-stabilized peptide conjugates in the prevention and treatment of an Ebolavirus infection or disease in a subject (e.g., human, non-human primate, or fruit bat). The disclosure also relates to methods of using such structurally-stabilized peptides and conjugates in the prevention and treatment of a Marburg virus infection, a Bombali ebolavirus infection, or a Mengla dianlovirus infection in a subject.

A conjugate comprising a structurally-stabilized peptide and polyethylene glycol (PEG) and/or cholesterol or thiocholesterol;

wherein the PEG and/or cholesterol or thiocholesterol are linked to the C-terminal amino acid of the structurally-stabilized peptide;
wherein the structurally-stabilized peptide comprises:
(a) an amino acid sequence comprising 28-32 contiguous amino acids of the sequence set forth in SEQ ID NO:10 with two to five amino acid substitutions relative to the sequence set forth in SEQ ID NO:10;
wherein two of the two to five amino acid substitutions are with α, α-disubstituted non-natural amino acids with olefinic side chains cross-linked to each other at positions of the sequence set forth in SEQ ID NO:
10 selected from (wherein position 1 is the N-terminal threonine and position 32 is the C-terminal valine of SEQ ID NO:
10):
(i) positions 17 and 24,
(ii) positions 18 and 25,
(iii) positions 19 and 26,
(iv) positions 20 and 27,
(v) positions 21 and 28,
(vi) positions 22 and 29,
(vii) positions 23 and 30,
(viii) positions 24 and 31, or
(ix) positions 25 and 32;
or
(b) an amino acid sequence comprising 28-32 contiguous amino acids of the sequence set forth in SEQ ID NO:10 with two to five amino acid substitutions relative to the sequence set forth in SEQ ID NO:10 and comprising the formula:
or a pharmaceutically acceptable salt thereof;
wherein each R1 and R2 is H or a C1 to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl, any of which is substituted or unsubstituted;
wherein each R3 is independently alkane alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted;
wherein z is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
and
wherein:
(i) each [Xaa]x is KNITDK (SEQ ID NO:
55), or a variant thereof having one amino acid substitution;
(ii) each [Xaa]x is NITDKI (SEQ ID NO:
58), or a variant thereof having one amino acid substitution;
(iii) each [Xaa]x is ITDKID (SEQ ID NO:
61), or a variant thereof having one amino acid substitution;
(iv) each [Xaa]x is TDKIDQ (SEQ ID NO:
64), or a variant thereof having one amino acid substitution;
(v) each [Xaa]x is DKIDQI (SEQ ID NO:
67), or a variant thereof having one amino acid substitution;
(vi) each [Xaa]x is KIDQII (SEQ ID NO:
70), or a variant thereof having one amino acid substitution;
(vii) each [Xaa]x is IDQIIH (SEQ ID NO:
73), or a variant thereof having one amino acid substitution;
(viii) each [Xaa]x is DQIIHD (SEQ ID NO:
76), or a variant thereof having one amino acid substitution;
or
(ix) each [Xaa]x is QIIHDF (SEQ ID NO:
79), or a variant thereof having one amino acid substitution;
wherein the conjugate binds to a 5 helix bundle or fusion bundle intermediate of EBOV GP2 and/or wherein the conjugate inhibits infection of a cell by EBOV in pseudovirus and/or live EBOV virus assay and/or prevents infection of a cell by EBOV in a pseudovirus and/or a live EBOV virus assay;
and
optionally wherein the structurally-stabilized peptide is 28 to 40 amino acids in length, optionally 28 to 35 amino acids in length.

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Ebolavirus surface glycoprotein peptides, conjugates, and uses thereof

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Ebolavirus surface glycoprotein peptides, conjugates, and uses thereof

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Abstract

Claims36