US 12,138,312 B2
Cell-penetrating peptides for antisense delivery
Justin M. Wolfe, Cambridge, MA (US); Colin M. Fadzen, Cambridge, MA (US); Zi-Ning Choo, Cambridge, MA (US); Rebecca L. Holden, Cambridge, MA (US); Monica Yao, Cambridge, MA (US); Gunnar J. Hanson, Cambridge, MA (US); and Bradley L. Pentelute, Cambridge, MA (US)
Assigned to Sarepta Therapeutics, Inc., Cambridge, MA (US); and Massachusetts Institute of Technology, Cambridge, MA (US)
Appl. No. 16/756,616
Filed by Sarepta Therapeutics, Inc., Cambridge, MA (US); and Massachusetts Institute of Technology, Cambridge, MA (US)
PCT Filed Oct. 17, 2018, PCT No. PCT/US2018/056205
§ 371(c)(1), (2) Date Apr. 16, 2020,
PCT Pub. No. WO2019/079386, PCT Pub. Date Apr. 25, 2019.
Claims priority of provisional application 62/573,379, filed on Oct. 17, 2017.
Prior Publication US 2020/0316210 A1, Oct. 8, 2020
Int. Cl. A61K 47/65 (2017.01); A61K 31/713 (2006.01); A61K 47/64 (2017.01); C12N 15/11 (2006.01); C12N 15/113 (2010.01)
CPC A61K 47/65 (2017.08) [A61K 31/713 (2013.01); C12N 15/111 (2013.01); C12N 15/113 (2013.01); A61K 47/6455 (2017.08); C12N 2310/11 (2013.01); C12N 2310/3513 (2013.01)] 19 Claims
 
1. A peptide-oligonucleotide conjugate of Formula (I):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt thereof,
wherein:
A′ is selected from —NHCH2C(O)NH2, —N(C1-6-alkyl)CH2C(O)NH2,

OG Complex Work Unit Chemistry
 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

OG Complex Work Unit Chemistry
wherein R6 is selected from OH, SH, and NH2, or R6 is O, S, or NH, covalently linked to a solid support;
each R1 is independently selected from OH and —NR3R4, 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,

OG Complex Work Unit Chemistry
wherein
Q is —C(O)(CH2)6C(O)— or —C(O)(CH2)2S2(CH2)2C(O)—, and
R7 is —(CH2)2OC(O)N(R8)2, wherein R8 is —(CH2)6NHC(═NH)NH2, and
wherein L is covalently linked by an amide bond to the amino-terminus of J, and L is —C(O)(CH2)1-6—C1-6-heteroaromatic-(CH2)1-6C(O)—;
t is 5-27;
each J is independently at each occurrence, selected from the group consisting of arginine, glycine, leucine, alanine, phenylalanine, methionine, tryptophan, lysine, glutamine, glutamic acid, serine, proline, valine, isoleucine, cysteine, tyrosine, histidine, asparagine, aspartic acid, and threonine;
wherein at least one J is arginine;
G is covalently linked by an amide bond to the carboxy-terminus of J, and G is selected from H, —C(O)C1-6-alkyl, benzoyl, and stearoyl; and
wherein at least one of the following conditions is true:
1) A′ is

OG Complex Work Unit Chemistry
 or 2) E′ is

OG Complex Work Unit Chemistry
 
17. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.