Peptide oligonucleotide conjugates

Patent metadata

Field	Value
Publication number	US-12239715-B2
Application number	US-202318296697-A
Country	US
Kind code	B2
Filing date	Apr 6, 2023
Priority date	May 19, 2015
Publication date	Mar 4, 2025
Grant date	Mar 4, 2025

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.

First claim

What is claimed is:

1. A peptide-oligonucleotide-conjugate, or a pharmaceutically acceptable salt thereof, of Formula (I):

wherein:
z is 8-40;
each R 1 is independently selected from OH and —NR 3 R 4 , wherein each R 3 and R 4 are independently at each occurrence —C 1-6 alkyl;
each R 2 is independently selected from H, a nucleobase, and a nucleobase functionalized with a chemical protecting-group, wherein the nucleobase independently at each occurrence comprises pyridine, pyrimidine, triazinane, purine, or deaza-purine;
A′ is selected from —NHCH 2 C(O)NH 2 , —N(C 1-6 -alkyl)CH 2 C(O) NH 2 ,

R 5 is —C(O)(O-alkyl) x -OH, wherein x is 3-10 and each alkyl group is independently at each occurrence C 2-6 -alkyl, or R 5 is selected from —C(O)C 1-6 alkyl, trityl, monomethoxytrityl, —(C 1-6 -alkyl)R 6 , —(C 1-6 heteroalkyl)-R 6 , aryl-R 6 , heteroaryl-R 6 , —C(O)O—(C 1-6 alkyl)-R 6 , —C(O)O-aryl-R 6 , —C(O)O-heteroaryl-R 6 , and -L-(J) t —G;
R 6 is selected from OH, SH, and NH 2 , or R 6 is O, S, or NH, covalently linked to a solid support;
E′ is selected from H, —C 1-6 alkyl, —C(O)C 1-6 alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl,

Q is —C(O)(CH 2 ) 6 C(O)— or —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—,
R 7 is —(CH 2 ) 2 OC(O)N(R 8 ) 2 ;
R 8 is —(CH 2 ) 6 NHC(═NH)NH 2 ;
R 11 is selected from —OH and —NR 3 R 4 ;
-L-(J) t —G is selected from:

R is arginine;
d is 0 or 1; and
M is:

each R 10 is independently at each occurrence H or a halogen,
wherein at least one of the following conditions is true:
1) A′ is

2) E′ is -L-(J) t -G; or 3) E′ is

2. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E′ is selected from H, —C(O) CH 3 , trityl, 4-methoxytrityl, benzoyl, stearoyl, and -L-(J) t -G.

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

or
E′ is -L-(J) t -G.

4. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A′ is selected from —N(C 1-6 -alkyl)CH 2 C(O) NH 2 ,

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

and
E′ is selected from H, —C(O)CH 3 , trityl, 4-methoxytrityl, benzoyl, and stearoyl.

6. 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:

7. The peptide-oligonucleotide-conjugate of claim 6 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the Formula (Ia) and R 5 is —C(O)(O—CH 2 CH 2 ) 3 OH.

8. The peptide-oligonucleotide-conjugate of claim 6 , 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)CH 3 , benzoyl, and stearoyl.

9. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 10 is fluorine.

10. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein M is:

11. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 8-25.

12. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 10-20.

13. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein z is 17-21.

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

15. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is —N(CH 3 ) 2 .

16. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is a nucleobase independently at each occurrence selected from adenine, guanine, cytosine, 5-methyl-cytosine, thymine, uracil, and hypoxanthine.

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

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

19. 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 of Formula (V):

wherein R 14 is selected from:

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

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

and
d is 0.

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

M is

and
d is 1.

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

M is

Assignees

• Sarepta Therapeutics Inc

Inventors

• Hanson Gunnar J
• Zhou Ming

Classifications

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K38/00 Primary

  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 title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07K7/06

  having 5 to 11 amino acids · CPC title