Granted Patent
B2
US 12,258,423 · App. 16/950,540 · Granted Mar 25, 2025
Stapled and stitched polypeptides and uses thereof
Assignee:
PRESIDENT AND FELLOWS OF HARVARD COLLEGE
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Abstract
The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R 1a , R 1b , R 1c , R 2a , R 3a , R 2b , R 3b , R 4a , R 4b , R A , R Z , L 1a , L 1b , L 2 , L 3 , X AA , v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.
Claims (35)
1. An amino acid of Formula (D):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen; substituted or unsubstituted C 1-6 alkyl; or an amino protecting group;
L 1 is substituted or unsubstituted C 1-10 alkylene, or —C(═O)OR 6 —;
R A is hydrogen or an amino protecting group;
R B is hydrogen;
X 1 is N;
R 6 is C 1-6 alkylene; and
each of j and j1 is independently an integer between 1 and 10, inclusive, wherein when one of j and j1 is 2, the other is 1, or an integer between 3 and 10, inclusive.
2. The amino acid of claim 1 , wherein the amino acid is selected from the group consisting of:
or a salt thereof, wherein g1 is one to six.
3. The amino acid of claim 1 , wherein R 1 is an amino protecting group.
4. The amino acid of claim 1 , wherein R 1 is substituted or unsubstituted C 1-6 alkyl.
5. The amino acid of claim 1 , wherein R 1 is hydrogen.
6. The amino acid of claim 4 , wherein R A is an amino protecting group.
7. The amino acid of claim 1 , wherein represents a double bond.
8. The amino acid of claim 1 , wherein represents a triple bond.
9. The amino acid of claim 1 , wherein R 1 is an amino protecting group and R A is hydrogen.
10. The amino acid of claim 9 , wherein the amino acid protecting group is Fmoc.
11. The amino acid of claim 9 , wherein represents a double bond.
12. The amino acid of claim 10 , wherein represents a double bond.
13. An amino acid of Formula (D):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is an amino protecting group;
L 1 is a substituted or unsubstituted C 1-10 alkylene, or —C(═O)OR 6 —;
R A is cyclic or acyclic, branched or unbranched, substituted or unsubstituted aliphatic;
cyclic or acyclic, branched or unbranched, substituted or unsubstituted heteroaliphatic; or
substituted or unsubstituted heteroaryl;
R B is hydrogen;
X 1 is N;
R 6 is C 1-6 alkylene; and
each of j and j1 is independently an integer between 1 and 10, inclusive.
14. The amino acid of claim 13 , wherein represents a double bond.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Dec 1, 2020
From: VERDINE, GREGORY L.; HILINSKI, GERARD
To: PRESIDENT AND FELLOWS OF HARVARD COLLEGE
Reel/Frame 054506/0945 →
Continuity (4)
Division
14775315
Provisional Application
61779917
· Mar 13, 2013
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