ANTIVIRAL STRUCTURALLY-STAPLED SARS-CoV-2 PEPTIDE-CHOLESTEROL CONJUGATES AND USES THEREOF
AssigneeDana-Farber Cancer Institute, Inc.
InventorsLoren D. Walensky, Gregory H. Bird
Life of this patent
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Abstract
Disclosed herein are cross-linked peptides either alone or conjugated to PEG(n)-cholesterol (or thiocholesterol) moieties useful for interfering with and inhibiting or preventing coronavirus infection (e.g., infection by SARS-CoV-2). Also disclosed are methods of treating and/or preventing a coronavirus infection (e.g., COVID-19.
Claims40
A structurally-stabilized peptide comprising an amino acid sequence that is at least 85% identical to sequence set forth in SEQ ID NO:
- 6 (DISGINASVVNIQKEIDRLNEVAKNLNESLIDLQELGK), wherein amino acids at positions of SEQ ID NO:6 selected from (wherein position 1 is the N-terminal Aspartic Acid and position 38 is the C-terminal Lysine of SEQ ID NO:
- 6):
- (i) positions 14 and 21,
- (ii) positions 17 and 24,
- (iii) positions 21 and 28, or
- (iv) positions 24 and 31;
- are replaced by α, α-disubstituted non-natural amino acids with olefinic side chains whose side chains are cross-linked;
- wherein the structurally-stabilized peptide is 38 to 60 amino acids in length;
- and
- wherein the structurally-stabilized peptide inhibits infection of a cell by SARS-CoV-2 in pseudovirus and/or live SARS-CoV-2 virus assays and/or wherein the structurally-stabilized peptide prevents infection of a cell by SARS-CoV-2 in the pseudovirus and/or the live SARS-CoV-2 virus assays.
-14. (canceled)
-28. (canceled)
A conjugate comprising:
- a structurally-stabilized peptide of SEQ ID NO:
- 10 (DISGINASVVNIQ8EIDRLNXVAKNLNESLIDLQELGK), wherein 8 is a (R)-α-(7′-octenyl)alanine group or a (R)-α-(4′-pentenyl)alanine group, and X is a (S)-α-(4′-pentenyl)alanine group or a (S)-α-(7′-octenyl)alanine group;
- and
- a PEG(n)-cholesterol or a PEG(n)-thiocholesterol moiety linked to the C-terminal lysine of the structurally-stabilized peptide, wherein n is 1-36.
-40. (canceled)
A structurally-stabilized peptide 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;
- each R3 is independently alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted;
- z is 1;
- (a) each [Xaa]w is DISGINASVVNIQ (SEQ ID NO:
- 35), each [Xaa]x is EIDRLN (SEQ ID NO:
- 36), and each [Xaa]y is VAKNLNESLIDLQELGK (SEQ ID NO:
- 37);
- (b) each [Xaa]w is DISGINASVVNIQKEI (SEQ ID NO:
- 44), each [Xaa]x is RLNEVA (SEQ ID NO:
- 45), and each [Xaa]y is NLNESLIDLQELGK (SEQ ID NO:
- 46);
- (c) each [Xaa]w is DISGINASVVNIQKEIDRLN (SEQ ID NO:
- 56), each [Xaa]x is VAKNLN (SEQ ID NO:
- 57), and each [Xaa]y is SLIDLQELGK (SEQ ID NO:
- 58);
- or
- (d) each [Xaa]w is DISGINASVVNIQKEIDRLNEVA (SEQ ID NO:
- 65), each [Xaa]x is NLNESL (SEQ ID NO:
- 66), and each [Xaa]y is DLQELGK (SEQ ID NO:
- 67);
- and
- wherein the structurally-stabilized peptide inhibits infection of a cell by SARS-CoV-2 in in pseudovirus and/or live SARS-CoV-2 virus assays and/or wherein the structurally-stabilized peptide prevents infection of a cell by SARS-CoV-2 in the pseudovirus and/or the live SARS-CoV-2 virus assays.
-49. (canceled)
A structurally stabilized peptide comprising Formula I-A, wherein Formula I-A is defined by:
- or a pharmaceutically acceptable salt thereof;
- R3 is alkenylene;
- [Xaa]w is
- (SEQ ID NO:
- 35)
- DISGINASVVNIQ;
- [Xaa]x is
- (SEQ ID NO:
- 36)
- EIDRLN;
- and
- [Xaa]y is
- (SEQ ID NO:
- 37)
- VAKNLNESLIDLQELGK;
- wherein optionally the amino group of the N-terminal aspartic acid in [Xaa]w is replaced with —N(H)C(O)—(C1-4 alkyl), and optionally the carboxylic acid group of the C-terminal lysine in [Xaa]y is replaced with —C(O)NH2.
-64. (canceled)
-121. (canceled)
A method of making a structurally-stabilized peptide, the method comprising:
- (a) providing a peptide having the sequence set forth in SEQ ID NO:
- 6 or a variant thereof, and (b) cross-linking the peptide.
123-124. (canceled)
A method of synthesizing a conjugate comprising a heptad repeat domain 2 (HR2) polypeptide, the method comprising (a) providing the HR2 polypeptide;
- and (b) derivatizing a resin bound amine of the HR2 polypeptide with (i) PEG and/or (ii) cholesterol or thiocholesterol containing a carboxylic acid on a resin.
-150. (canceled)
A linker comprising:
- (a) a PEG(n)-thiocholesterol comprising the formula:
- wherein n is 1-36;
- or
- (b) a PEG(n)-cholesterol comprising the formula:
- wherein n is 1-36.
-154. (canceled)
Dependencies are inferred from the claim text.