Peptide oligonucleotide conjugates

• US 10,675,356 B2
• Filed: 05/19/2016
• Issued: 06/09/2020
• Est. Priority Date: 05/19/2015
• Status: Active Grant

• Current Assignee: Sarepta Therapeutics, Inc.
• Original Assignee: Sarepta Therapeutics, Inc.
• Inventors: Hanson, Gunnar J., Zhou, Ming
• Primary Examiner(s): Katakam, Sudhakar
• Application Number:
  US15/574,734
• Publication Number:
  US 20180214567A1
• Time in Patent Office: 1,482 Days
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/645 Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Provided herein are oligonucleotides, peptides, and peptide-oligonucleotide-conjugates. Also provided herein are methods of treating a muscle disease, a viral infection, or a bacterial infection in a subject in need thereof, comprising administering to the subject oligonucleotides, peptides, and peptide-oligonucleotide-conjugates described herein.

Claims

1. A peptide-oligonucleotide-conjugate of Formula I:

2. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein E′

is selected from H, —

C_1-6 alkyl, —

C(O)C_1-6 alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, and

3. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein A′

is

4. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

A′

is selected from —

N(C_1-6-alkyl)CH₂C(O)NH₂,

5. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein E′

is selected from H, —

C(O)CH₃, trityl, 4-methoxytrityl, benzoyl, stearoyl, and

6. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein A′

is selected from —

N(C_1-6-alkyl)CH₂C(O)NH₂,

7. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein A′

is

8. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate of Formula I is a peptide-oligonucleotide-conjugate selected from:

9. The peptide-oligonucleotide-conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the formula (Ia) and R⁵ is —

C(O)(O—

CH₂CH₂)₃OH.

10. The peptide-oligonucleotide-conjugate of claim 8, or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the formula (Ib) and E′

is selected from H, C_1-6 alkyl, —

C(O)CH₃, benzoyl, and stearoyl.

11. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹⁰ is fluorine.

12. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

M is

13. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

J is independently selected from cysteine and arginine.

14. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

two J groups are cysteine.

15. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

z is 8-25.

16. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R¹ is N(CH₃)₂.

17. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

each R² is a nucleobase independently at each occurrence selected from adenine, guanine, cytosine, 5-methyl-cytosine, thymine, uracil, and hypoxanthine.

18. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is selected from —

NH(CH₂)_1-6C(O)—

, —

NH(CH₂)₅C(O)NH(CH₂)₂C(O)—

, and

19. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is selected from glycine and

20. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is glycine.

21. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

G is selected from H, C(O)CH₃, benzoyl, and stearoyl.

22. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

G is H or —

C(O)CH₃.

23. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

G is —

C(O)CH₃.

24. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein d is 1.

25. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein d is 0.

26. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein

27. The peptide-oligonucleotide-conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is selected from:

28. The peptide-oligonucleotide-conjugate of claim 27, wherein G is H.

29. The peptide-oligonucleotide-conjugate of claim 27, wherein G is —

C(O)CH₃.

30. The peptide-oligonucleotide-conjugate of claim 27, wherein E′

is H.

31. The peptide-oligonucleotide-conjugate of claim 27, wherein E′

is —

C(O)CH₃.

32. The peptide-oligonucleotide-conjugate of claim 27, wherein E′

and G are —

C(O)CH₃.

33. The peptide-oligonucleotide-conjugate of claim 27, wherein G is —

C(O)CH₃ and E′

is H.

34. The peptide-oligonucleotide-conjugate of claim 1, wherein the conjugate is comprised of a structure of Formula V: