IP Library › Granted Patent US 12,391,733
Granted Patent B2
US 12,391,733 · App. 18/590,636 · Granted Aug 19, 2025

Stapled intracellular-targeting antimicrobial peptides to treat infection

Inventors: Loren D. Walensky (Newton, MA); Rida Mourtada (Brookline, MA)
Assignee: Dana-Farber Cancer Institute, Inc.
C07K14/461A61K38/08A61K38/10A61K38/1703A61K38/1706A61K38/1709A61K38/1767A61K45/06C07K7/06C07K7/08C07K14/43504C07K14/463C07K14/47
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Quick Facts
Patent No.
US 12,391,733
App. No.
18/590,636
Granted
Aug 19, 2025
Kind
B2
Abstract

Structurally stabilized, e.g., stapled, peptides with the ability to translocate through microbial cell membranes to the interior of microbial cells and exert a biological activity there are provided, as are methods of designing, making and using such peptides.

Claims (146)

1. A stapled peptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence:

(SEQ ID NO: 41)

TRSSRAGLQWPVX 1 RVHX 2 LLRK,

(SEQ ID NO: 37)

TRSSRAGLQWPVGRVHX 1 LLRX 2 ,

(SEQ ID NO: 39)

TRSSRAGLQWPVGRX 1 HRLX 2 RK,

(SEQ ID NO: 40)

TRSSRAGLQWPVGX 1 VHRX 2 LRK,

(SEQ ID NO: 44)

TRSSRAGX 1 QWPX 2 GRVHRLLRK,

(SEQ ID NO: 45)

TRSSX 1 AGLX 2 WPVGRVHRLLRK,

(SEQ ID NO: 46)

TRSX 1 RAGX 2 QWPVGRVHRLLRK,

(SEQ ID NO: 48)

TX 1 SSRX 2 GLQWPVGRVHRLLRK,

(SEQ ID NO: 49)

X 1 RSSX 2 AGLQWPVGRVHRLLRK,

(SEQ ID NO: 50)

TRSSRAGLQWPVGX 3 VHRLLRX 4 ,

(SEQ ID NO: 51)

TRSSRAGLQWPVX 3 RVHRLLX 4 K,

(SEQ ID NO: 52)

TRSSRAGLQWPX 3 GRVHRLX 4 RK,

(SEQ ID NO: 53)

TRSSRAGLX 3 WPVGRVX 4 RLLRK,

(SEQ ID NO: 54)

TRSSRAGX 3 QWPVGRX 4 HRLLRK,

(SEQ ID NO: 56)

TRSSRX 3 GLQWPVX 4 RVHRLLRK,

(SEQ ID NO: 58)

TX 3 SSRAGLX 4 WPVGRVHRLLRK,

or

(SEQ ID NO: 59)

X 3 RSSRAGX 4 QWPVGRVHRLLRK,

wherein each of X 1 , X 2 , X 3 , and X 4 is a non-natural amino acid,

wherein X 1 and X 2 are cross-linked to each other where present, and

wherein X 3 and X 4 are cross-linked to each other where present.

2. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein each of X 1 , X 2 , X 3 , and X 4 is independently an α, α-disubstituted non-natural amino acid comprising an olefinic side chain.

3. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein each of X 1 and X 2 , and X 4 is(S)-2-(4′-pentenyl) alanine, and wherein X 3 is (R)-2-(7′-octenyl) alanine.

4. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , which is 21 to 30 amino acids in length.

5. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the pharmaceutically acceptable salt is an acetate, a citrate, a fumarate, a maleate, a succinate, a sulfate, or a malonate.

6. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , consisting of the amino acid sequence:

(SEQ ID NO: 41)

TRSSRAGLQWPVX 1 RVHX 2 LLRK,

(SEQ ID NO: 37)

TRSSRAGLQWPVGRVHX 1 LLRX 2 ,

(SEQ ID NO: 39)

TRSSRAGLQWPVGRX 1 HRLX 2 RK,

(SEQ ID NO: 40)

TRSSRAGLQWPVGX 1 VHRX 2 LRK,

(SEQ ID NO: 44)

TRSSRAGX 1 QWPX 2 GRVHRLLRK,

(SEQ ID NO: 45)

TRSSX 1 AGLX 2 WPVGRVHRLLRK,

(SEQ ID NO: 46)

TRSX 1 RAGX 2 QWPVGRVHRLLRK,

(SEQ ID NO: 48)

TX 1 SSRX 2 GLQWPVGRVHRLLRK,

(SEQ ID NO: 49)

X 1 RSSX 2 AGLQWPVGRVHRLLRK,

(SEQ ID NO: 50)

TRSSRAGLQWPVGX 3 VHRLLRX 4 ,

(SEQ ID NO: 51)

TRSSRAGLQWPVX 3 RVHRLLX 4 K,

(SEQ ID NO: 52)

TRSSRAGLQWPX 3 GRVHRLX 4 RK,

(SEQ ID NO: 53)

TRSSRAGLX 3 WPVGRVX 4 RLLRK,

(SEQ ID NO: 54)

TRSSRAGX 3 QWPVGRX 4 HRLLRK,

(SEQ ID NO: 56)

TRSSRX 3 GLQWPVX 4 RVHRLLRK,

(SEQ ID NO: 58)

TX 3 SSRAGLX 4 WPVGRVHRLLRK,

or

(SEQ ID NO: 59)

X 3 RSSRAGX 4 QWPVGRVHRLLRK,

wherein each of X 1 , X 2 , X 3 , and X 4 is a non-natural amino acid,

wherein X 1 and X 2 are cross-linked to each other where present, and

wherein X 3 and X 4 are cross-linked to each other where present.

7. The stapled peptide or pharmaceutically acceptable salt thereof of claim 6 , wherein each of X 1 , X 2 , X 3 , and X 4 is independently an α, α-disubstituted non-natural amino acid comprising an olefinic side chain.

8. The stapled peptide or pharmaceutically acceptable salt thereof of claim 6 , wherein each of X 1 and X 2 , and X 4 is(S)-2-(4′-pentenyl) alanine, and wherein X 3 is (R)-2-(7′-octenyl) alanine.

9. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , wherein the stapled peptide or pharmaceutically acceptable salt thereof is dihydroxylated.

10. The stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , which is linked to an antibiotic or methotrexate.

11. A pharmaceutical composition comprising the stapled peptide or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising the stapled peptide or pharmaceutically acceptable salt thereof of claim 3 , and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising the stapled peptide or pharmaceutically acceptable salt thereof of claim 8 , and a pharmaceutically acceptable carrier.

14. A method of treating a bacterial infection in a human subject in need thereof, the method comprising administering a therapeutically—effective amount of the stapled peptide or pharmaceutically acceptable salt thereof of claim 1 to the human subject.

15. A method of making a stapled peptide or pharmaceutically acceptable salt thereof, the method comprising:

(a) providing a peptide comprising the amino acid sequence:

(SEQ ID NO: 41)

TRSSRAGLQWPVX 1 RVHX 2 LLRK,

(SEQ ID NO: 37)

TRSSRAGLQWPVGRVHX 1 LLRX 2 ,

(SEQ ID NO: 39)

TRSSRAGLQWPVGRX 1 HRLX 2 RK,

(SEQ ID NO: 40)

TRSSRAGLQWPVGX 1 VHRX 2 LRK,

(SEQ ID NO: 44)

TRSSRAGX 1 QWPX 2 GRVHRLLRK,

(SEQ ID NO: 45)

TRSSX 1 AGLX 2 WPVGRVHRLLRK,

(SEQ ID NO: 46)

TRSX 1 RAGX 2 QWPVGRVHRLLRK,

(SEQ ID NO: 48)

TX 1 SSRX 2 GLQWPVGRVHRLLRK,

(SEQ ID NO: 49)

X 1 RSSX 2 AGLQWPVGRVHRLLRK,

(SEQ ID NO: 50)

TRSSRAGLQWPVGX 3 VHRLLRX 4 ,

(SEQ ID NO: 51)

TRSSRAGLQWPVX 3 RVHRLLX 4 K,

(SEQ ID NO: 52)

TRSSRAGLQWPX 3 GRVHRLX 4 RK,

(SEQ ID NO: 53)

TRSSRAGLX 3 WPVGRVX 4 RLLRK,

(SEQ ID NO: 54)

TRSSRAGX 3 QWPVGRX 4 HRLLRK,

(SEQ ID NO: 56)

TRSSRX 3 GLQWPVX 4 RVHRLLRK,

(SEQ ID NO: 58)

TX 3 SSRAGLX 4 WPVGRVHRLLRK,

or

(SEQ ID NO: 59)

X 3 RSSRAGX 4 QWPVGRVHRLLRK,

wherein each of X 1 , X 2 , X 3 , and X 4 is an α, α-disubstituted non-natural amino acid comprising an olefinic side chain; and

(b) performing a ring-closing metathesis reaction on the peptide, thereby making the stapled peptide.

16. A stapled peptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence:

(SEQ ID NO: 41)

TRSSRAGLQWPVX 1 RVHX 2 LLRK,

wherein each of X 1 and X 2 is a non-natural amino acid, and

wherein X 1 and X 2 are cross-linked to each other.

17. The stapled peptide or pharmaceutically acceptable salt thereof of claim 16 , wherein each of X 1 and X 2 is independently an α, α-disubstituted non-natural amino acid comprising an olefinic side chain.

18. The stapled peptide or pharmaceutically acceptable salt thereof of claim 16 , wherein each of X 1 and X 2 is(S)-2-(4′-pentenyl) alanine.

19. A pharmaceutical composition comprising the stapled peptide of claim 16 and a pharmaceutically acceptable carrier.

20. A method of treating a bacterial infection in a human subject in need thereof, the method comprising administering a therapeutically-effective amount of the stapled peptide or pharmaceutically acceptable salt thereof of claim 16 to the human subject.

21. The method of claim 14 , wherein the bacterial infection is caused by a Gram-positive bacterium.

22. The method of claim 14 , wherein the bacterial infection is caused by a Gram-negative bacterium.

23. The method of claim 14 , wherein the bacterial infection is caused by E. coli, B. cereus, P. aeruginosa, S. aureus , or methicillin-resistant S. aureus.

24. The method of claim 14 , further comprising administering to the human subject a therapeutically-effective amount of an antibiotic.

25. The method of claim 20 , wherein the bacterial infection is caused by a Gram-positive bacterium.

26. The method of claim 20 , wherein the bacterial infection is caused by a Gram-negative bacterium.

27. The method of claim 20 , wherein the bacterial infection is caused by E. coli, B. cereus, P. aeruginosa, S. aureus , or methicillin-resistant S. aureus.

28. The method of claim 20 , further comprising administering to the human subject a therapeutically-effective amount of an antibiotic.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 29, 2024
From: WALENSKY, LOREN D.; MOURTADA, RIDA
To: DANA-FARBER CANCER INSTITUTE, INC.
Reel/Frame 066597/0277 →
Continuity (4)
Continuation 16813528 · Mar 9, 2020
Continuation 15445502 · Feb 28, 2017
Provisional Application 62301426 · Feb 29, 2016
Related Publication 20240343765A1 · Oct 17, 2024
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