Chimeric peptides for antisense delivery

A chimeric peptide-oligonucleotide conjugate of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• A′ is selected from —NHCH2C(O)NH2, —N(C1-6-alkyl)CH2C(O)NH2,
• wherein
• R5 is —C(O)(O-alkyl)x-OH, wherein x is 3-10 and each alkyl group is, independently at each occurrence, C2-6-alkyl,
• or R5 is selected from —C(O)C1-6-alkyl, trityl, monomethoxytrityl, —(C1-6-alkyl)-R6, —(C1-6-heteroalkyl)-R6, aryl-R6, heteroaryl-R6, —C(O)O—(C1-6-alkyl)-R6, —C(O)O-aryl-R6, —C(O)O-heteroaryl-R6, and
• wherein R6 is selected from OH, SH, and NH2, or R6 is O, S, or NH, each of which are covalently-linked to a solid support;
• each R1 is independently selected from OH and —N(R3)(R4), wherein each R3 and R4 are, independently at each occurrence, —C1-6-alkyl;
• each R2 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 C3-6-heterocyclic ring selected from pyridine, pyrimidine, triazinane, purine, and deaza-purine;
• z is 8-40;
• and
• E′ is selected from H, —C1-6-alkyl, —C(O)C1-6-alkyl, benzoyl, stearoyl, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl,
• wherein
• Q is —C(O)(CH2)6C(O)— or —C(O)(CH2)2S2(CH2)2C(O)—;
• R7 is —(CH2)2OC(O)N(R′)2, wherein R8 is —(CH2)6NHC(═NH)NH2;
• L is —C(O)(CH2)1-6—C1-6-heteroaromatic-(CH2)1-6C(O), wherein L is covalently-linked by an amide bond to the amino-terminus of J;
• J is 2, 3, 4, or 5 covalently-linked cell-penetrating peptides;
• G is selected from H, —C(O)C1-6-alkyl, benzoyl, and stearoyl, wherein G is covalently-linked by an amide bond to the carboxy-terminus of J;
• and
• wherein at least one of the following conditions is true:
• 1) A′ is
• or 2) E′ is
• wherein at least one of the cell-penetrating peptides is an amphipathic peptide and at least one of the cell-penetrating peptides is an oligoarginine peptide.