Peptide oligonucleotide conjugates

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 of claim 1 , or a pharmaceutically acceptable salt thereof, wherein d is 1.

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

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

is selected from:

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

wherein

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

E′ is selected from H and —C(O)CH 3 .

22. The peptide-oligonucleotide-conjugate of claim 21 , wherein E′ and G are —C(O)CH 3 .

23. The peptide-oligonucleotide-conjugate of claim 21 , wherein G is —C(O)CH 3 and E′ is H.

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

z is 10-20.

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

z is 17-21.

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

z is about 18.