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)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 . (canceled)

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

or E′ is

4 - 33 . (canceled)

34 . A pharmaceutical composition comprising the peptide-oligonucleotide-conjugate according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

35 . A method of treating a muscle disease, a viral infection, or a bacterial infection in a subject in need thereof, comprising administering to the subject 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

36 . The method of claim 35 , wherein a viral infection in the subject is treated and the viral infection is caused by a virus is selected from the group consisting of marburg virus, ebola virus, influenza virus, and dengue virus.

37 . The method of claim 35 , wherein a muscle disease in the subject is treated.

38 . The method of claim 35 , wherein a bacterial infection in the subject is treated and the bacterial infection is caused by Mycobacterium tuberculosis.

39 . The method of claim 35 , where in the subject is a human.

40 . The method of claim 35 , wherein E′ is selected from H, —C(O)CH 3 , trityl, 4-methoxytrityl, benzoyl, stearoyl, and -L-(J) t -G.

41 . The method of claim 35 , wherein A′ is selected from —N(C 1-6 -alkyl) CH 2 C(O)NH 2 ,

42 . The method of claim 35 , wherein E′ and G are —C(O)CH 3 .

43 . The method of claim 35 , wherein G is —C(O)CH 3 and E′ is H.

44 . The method of claim 35 , wherein the peptide-oligonucleotide-conjugate of Formula (I) is a peptide-oligonucleotide-conjugate selected from:

45 . The method of claim 44 , wherein the peptide-oligonucleotide-conjugate is of the Formula (Ia) and R 5 is —C(O)(O—CH 2 CH 2 ) 3 OH.

46 . The method of claim 44 , 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.

47 . The method of claim 35 , wherein each R 1 is —N(CH 3 ) 2 .

48 . The method of claim 35 , wherein the peptide-oligonucleotide-conjugate of Formula (I) is a peptide-oligonucleotide-conjugate of Formula (V):

wherein R 14 is selected from:

49 . The method of claim 48 , wherein R 14 is:

50 . A peptide selected from the group consisting of:

wherein

Ac is acetyl;

Cys is cysteine;

Gly is glycinyl or Gly-P3P;

R is arginine; and