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US 2026/0226109 A1Published application
Stabilized peptides for covalent binding to target protein
AssigneeDana-Farber Cancer Institute, Inc.
InventorsLoren D. Walensky, Gregory H. Bird
Life of this patent
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Abstract
Provided herein is a platform technology for designing stabilized peptides that covalently bind their target protein and thereby inhibit the activity of the target protein. Also provided are exemplary stabilized peptides that can be used for covalent modification of their target proteins.
Claims20
A method for identifying an amino acid or a position for modification in a polypeptide to facilitate covalent binding to a target protein that the polypeptide binds to, the method comprising:
- (a) providing a protein comprising a cysteine residue, wherein the cysteine residue is in a region of the protein that binds a polypeptide;
- providing the polypeptide that binds the target protein;
- determining that the sulfhydryl group of the cysteine residue in the target protein is at a distance between 0.1 Å and 15 Å from the alpha carbon of an amino acid in the polypeptide, wherein the alpha carbon is on the first, the last or any internal amino acid of the polypeptide;
- and
- identifying the amino acid as the amino acid to substitute with a non-natural amino acid or other chemical moiety linked to a stapled peptide comprising an electrophilic group;
- or
- identifying the position of the amino acid in the polypeptide as the position to append an electrophilic moiety,
- thereby facilitating covalent binding to the protein;
- or
- (b) identifying an amino acid or a position in the polypeptide as the amino acid to modify by substitution with a non-natural amino acid or other chemical moiety linked to a peptide comprising an electrophilic group, or identifying the position of the amino acid in the polypeptide as the position to append an electrophilic moiety in order to facilitate covalent binding to an interacting protein, the alpha carbon of the amino acid having been previously determined to be between 0.1 Å and 15 Å from the sulfhydryl group of a cysteine residue in the interacting protein, wherein the cysteine residue is in a region of the interacting protein that binds the polypeptide, and wherein the alpha carbon of the amino acid is on the first, the last or any internal amino acid of the polypeptide.
7 more elements
-60. (canceled)
An internally cross-linked peptide, wherein:
- (a) the internally cross-linked peptide comprises Formula I or a pharmaceutically acceptable salt thereof,
- wherein;
- each Xaa is independently a natural amino acid or a non-natural amino acid;
- R1 and R2 are independently H or a C1 to C10 alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, or heterocyclylalkyl;
- R3 is alkylene, alkenylene or alkynylene (e.g., a C6, C7, or C11 alkenylene) substituted with 1-6 R4;
- x is 2, 3 or 6;
- w and y are independently an integer from 5-20;
- provided that:
- when x is 2, R3 is C4-13 alkylene, alkenylene or alkynylene;
- when x is 3, R3 is C4-13 alkylene, alkenylene or alkynylene;
- and when x is 6, R3 is C4-13 alkylene, alkenylene or alkynylene and provided that the sum of x, w and y is at least 12;
- wherein the side chain of at least one Xaa replaced by an electrophilic group;
- and
- wherein the internally cross-linked peptide comprises the amino acid sequence of any one of SEQ ID NOs:
- 9-12, 24-33, 35-45, 47-49, 51, 53-56, 59, 60, 64-67, 70-75, 76-96, and 98-117, except for 0 to 3 amino acid substitutions.
12 more elements
-68. (canceled)
A stapled peptide comprising:
- (a) the amino acid sequence set forth in any one of SEQ ID NOs:
- 24-33, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 24-33, wherein the stapled peptide binds to mediator of RNA polymerase II transcription subunit 22;
- (b) the amino acid sequence set forth in any one of SEQ ID NOs:
- 35-45, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 35-45, wherein the stapled peptide binds to FADD;
- (c) the amino acid sequence set forth in any one of SEQ ID NOs:
- 47-49, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 47-49, wherein the stapled peptide binds to myosin-X;
- (d) the amino acid sequence set forth in any one of SEQ ID NOs:
- 51 and 53-56, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 51 and 53-56, wherein the stapled peptide binds to PDCD4;
- (e) the amino acid sequence set forth in SEQ ID NO:
- 59 or 60, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 59 or 60, wherein the stapled peptide binds to DAXX;
- (f) the amino acid sequence set forth in any one of SEQ ID NOs:
- 64-67, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 64-67, wherein the stapled peptide binds to p300;
- (g) the amino acid sequence set forth in any one of SEQ ID NOs:
- 70-75, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 70-75, wherein the stapled peptide binds to tryptophanyl-tRNA synthetase;
- or
- (h) the amino acid sequence set forth in any one of SEQ ID NOs:
- 76-96 and 98-116, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 76-96 and 98-116, wherein the stapled peptide binds to RAS;
- and
- wherein the non-natural electrophile containing amino acid in the amino acid sequence set forth in any one of SEQ ID NOs:
- 24-33, 35-45, 47-49, 51, 53-56, 59, 60, 64-67, 70-75, 76-96, and 98-116 is present.
25 more elements
A peptide comprising:
- (a) the amino acid sequence set forth in any one of SEQ ID NOs:
- 10-12, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in any one of SEQ ID NOs:
- 10-12, wherein the peptide binds to BAX;
- (b) the amino acid sequence set forth in SEQ ID NO:
- 23, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 23, wherein the peptide binds to eiF4E;
- (c) the amino acid sequence set forth in SEQ ID NO:
- 52, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 52, wherein the peptide binds to PDCD4;
- (d) the amino acid sequence set forth in SEQ ID NO:
- 58 or 61, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 58 or 61, wherein the peptide binds to DAXX;
- (e) the amino acid sequence set forth in SEQ ID NO:
- 63, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 63, wherein the peptide binds to p300;
- (f) the amino acid sequence set forth in SEQ ID NO:
- 69, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 69, wherein the peptide binds to tryptophanyl-tRNA synthetase;
- or
- (g) the amino acid sequence set forth in SEQ ID NO:
- 97 or 117, except for zero to three amino acid substitutions relative to the amino acid sequence set forth in SEQ ID NO:
- 97 or 117, wherein the peptide binds to RAS;
- and
- wherein the non-natural electrophile containing amino acid in the amino acid sequence set forth in any one of SEQ ID NOs:
- 10-12, 23, 52, 58, 61, 63, 69, 97, and 117 is present.
22 more elements
Dependencies are inferred from the claim text.