Peptide oligonucleotide conjugates

Patent metadata

Field	Value
Publication number	US-11672871-B2
Application number	US-202117403403-A
Country	US
Kind code	B2
Filing date	Aug 16, 2021
Priority date	May 19, 2015
Publication date	Jun 13, 2023
Grant date	Jun 13, 2023

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 of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
A′ is selected from —NHCH 2 C(O)NH 2 , —N(C 1-6 -alkyl)CH 2 C(O)NH 2 ,

 wherein
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)O 1-6 alkyl, trityl, monomethoxytrityl, —(O 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

wherein R 6 is selected from OH, SH, and NH 2 , or R 6 is O, S, or NH, covalently linked to a solid support;

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 a C 3-6 heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine;
z is 8-38; and
E′ is selected from H, —C 1-6 alkyl, —C(O)C 1-6 alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl,

wherein
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 , wherein R 8 is —(CH 2 ) 6 NHC(═NH)NH 2 , and
R 11 is selected from OH and —NR 3 R 4 ,

wherein L is covalently linked by an amide bond to the carboxy-terminus of J, and L is selected from —NH(CH 2 ) 1-6 C(O)—, —NH(CH 2 ) 1-6 C(O)NH(CH 2 ) 1-6 C(O)—, and

t is 4-9;
each J is independently at each occurrence selected from an amino acid of the structure

wherein:
r and q are each independently 0, 1, 2, 3, or 4; and
each R 9 is independently at each occurrence selected from H, an amino acid side-chain, and an amino acid side-chain functionalized with a chemical protecting-group,
wherein two or more amino acid side-chain groups of R 9 independently at each occurrence comprise a sulfur, wherein two of the sulfur atoms, together with the atoms to which they are attached, form the structure

wherein d is 0 or 1, and M is selected from:

wherein each R 19 is independently at each occurrence H or a halogen; and
G is covalently linked to the amino-terminus of J, and G is selected from
H, —C(O)O 1-6 alkyl, benzoyl, and stearoyl, and

wherein at least one of the following conditions is true:

2. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein E′ is selected from H, —O 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)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 1 , 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 1 , or a pharmaceutically acceptable salt thereof, wherein the peptide-oligonucleotide-conjugate is of the formula (Ib) and E′ is selected from H, O 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
J is independently selected from cysteine and arginine.

12. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
two J groups are cysteine.

13. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
z is 15-25.

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

15. 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.

16. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
L is selected from —NH(CH 2 ) 1-6 C(O)—, —NH(CH 2 ) 5 C(O)NH(CH 2 ) 2 C(O)—, and

17. The peptide-oligonucleotide-conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
G is selected from H, C(O)CH 3 , benzoyl, and stearoyl.

18. The peptide-oligonucleotide-conjugate

Assignees

• Sarepta Therapeutics Inc

Inventors

• Hanson Gunnar J
• Zhou Ming

Classifications

• A61P31/04

  Antibacterial agents · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• C07K7/08

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

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K47/18

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