Peptide oligonucleotide conjugates

Patent metadata

Field	Value
Publication number	US-11097011-B2
Application number	US-202016860292-A
Country	US
Kind code	B2
Filing date	Apr 28, 2020
Priority date	May 19, 2015
Publication date	Aug 24, 2021
Grant date	Aug 24, 2021

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 method of treating Duchenne Muscular Dystrophy in a subject in need thereof, comprising administering to the subject a peptide-oligonucleotide-conjugate of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
A’ is selected from —NHCH 2 C(O)N H 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)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

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 8-40; 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 10 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)C 1-6 alkyl, benzoyl, and stearoyl, and
wherein at least one of the following conditions is true:
1) A′ is

2) E′ is

or 3) E′ is

2. The method of claim 1 , wherein
A′ is selected from —N(C 1-6 -alkyl)CH 2 C(O)NH 2 ,

3. The method of claim 1 , wherein E′ is selected from H, —C(O)CH 3 , trityl, 4-methoxytrityl, benzoyl, stearoyl, and

4. The method of claim 1 , wherein A′ is

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

5. The method of claim 1 , wherein the peptide-oligonucleotide-conjugate of Formula I is a peptide-oligonucleotide-conjugate selected from:

6. The method of claim 1 , wherein the peptide-oligonucleotide-conjugate is of the formula (Ia) and R 5 is —C(O)(O—CH 2 CH 2 ) 3 OH.

7. The method of claim 1 , 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.

8. The method of claim 1 , wherein M is

9. The method of claim 1 , wherein J is independently selected from cysteine and arginine.

10. The method of claim 1 , wherein each R 1 is N(CH 3 ) 2 .

11. The method of claim 1 , wherein L is selected from glycine and

12. The method of claim 1 , wherein L is glycine.

13. The method of claim 1 , wherein G is H or —C(O)C H 3 .

14. The method of claim 1 , wherein G is —C(O)CH 3 .

15. The method of claim 1 , wherein d is 1.

16. The method of claim 1 , wherein

is selected from:

17. The method of claim 1 , wherein the peptide-oligonucleotide-conjugate is selected from:

wherein
G is selected from H and —C(O)CH 3 , an

Assignees

• Sarepta Therapeutics Inc

Inventors

• Hanson Gunnar J
• Zhou Ming

Classifications

• A61P21/04

  for myasthenia gravis · CPC title

• A61K47/64 Primary

  Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65) · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61P21/00

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

• C07K7/08

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