US 12,168,059 B2
Trimeric peptides for antisense delivery
Justin Wolfe, Cambridge, MA (US); Colin M. Fadzen, Cambridge, MA (US); Bradley L. Pentelute, Cambridge, MA (US); and Gunnar J. Hanson, Cambridge, MA (US)
Assigned to Sarepta Therapeutics, Inc., Cambridge, MA (US); and Massachusetts Institute of Technology, Cambridge, MD (US)
Appl. No. 17/264,163
Filed by Sarepta Therapeutics, Inc., Cambridge, MA (US); and Massachusetts Institute of Technology, Cambridge, MA (US)
PCT Filed Jul. 29, 2019, PCT No. PCT/US2019/043920
§ 371(c)(1), (2) Date Jan. 28, 2021,
PCT Pub. No. WO2020/028254, PCT Pub. Date Feb. 6, 2020.
Claims priority of provisional application 62/711,894, filed on Jul. 30, 2018.
Prior Publication US 2021/0290772 A1, Sep. 23, 2021
Int. Cl. A61K 47/64 (2017.01); A61K 47/54 (2017.01); C12N 15/113 (2010.01)
CPC A61K 47/6455 (2017.08) [A61K 47/549 (2017.08); C12N 15/113 (2013.01); C12N 2310/11 (2013.01); C12N 2310/3233 (2013.01); C12N 2310/3513 (2013.01)] 23 Claims
 
1. A trimeric peptide-oligonucleotide conjugate of Formula I:

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or a pharmaceutically acceptable salt thereof,
wherein:
A′ is selected from —N(H)CH2C(O)NH2, —N(C1-6-alkyl)CH2C(O)NH2,

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 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

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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, at each occurrence, 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,

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wherein
Q is —C(O)(CH2)6C(O)— or —C(O)(CH2)2S2(CH2)2C(O)—;
R7 is —(CH2)2OC(O)N(R8)2, wherein R3 is —(CH2)6NHC(═NH)NH2;
L is —C(O)(CH2)1-6—C7-15-heteroaromatic-(CH2)1-6C(O)—, wherein L is covalently-linked by an amide bond to the amino-terminus of J;
J is —P1-L1-P2-L2-P3—;
P1, P2, and P3 are each independently a cell-penetrating peptide, wherein P1 and P2 each comprise at least one terminal or internal cysteine residue, and P2 comprises at least one terminal or internal lysine residue;

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M is

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and R10 is independently at each occurrence H or a halogen,
wherein L1 is covalently-linked to the side chain of a terminal or internal cysteine of P1 and P2;
L2 is —(CH2)1-6—C1-6-heteroaromatic-(CH2)1-6C(O)—, wherein L2 is covalently-linked to the side chain of a terminal or internal lysine on P2 and is covalently-linked by an amide bond to the amino-terminus of P3;
G is selected from H, —C(O)C1-6-alkyl, benzoyl, and stearoyl, wherein G is covalently-linked via —NH— to the carboxy-terminus of J; and
wherein at least one of the following conditions is true:

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