Granted Patent B2

US 12,624,068 · App. 16/474,686 · Granted May 12, 2026

Inventors: Shin Chung (Yongin-si, KR); Daram Jung (Hwaseong-Si, KR); Bongjun Cho (Yongin-Si, KR); Kangwon Jang (Yongin-Si, KR); Heungsik Yoon (Seongnam-Si, KR)

Assignee: OliPass Corporation

C07K14/003C07K7/02C12N15/113A61K38/00C12N2310/3181C12N2320/33

Abstract

Claims (38)

1 . A peptide nucleic acid derivative represented by Formula I, or a pharmaceutically acceptable salt thereof, for inducing exon skipping by targeting intron/exon or exon/intron junction of pre-mRNA:

wherein,

n is an integer between 11 and 20;

the compound of Formula I possesses at least a 10-mer complementary overlap with a 14-mer target splice site sequence that consists of 7-mer from intron and 7-mer from exon within a target pre-mRNA;

the compound of Formula I is fully complementary to the target pre-mRNA sequence, or partially complementary to the target pre-mRNA sequence with one or two mismatches;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X is hydrido radical;

Y is substituted or non-substituted alkyloxycarbonyl radical;

Z is amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from natural nucleobases including adenine, thymine, guanine, cytosine and uracil, and unnatural nucleobases; and

at least five of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV:

wherein,

R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are hydrido radical;

L 1 , L 2 and L 3 are a covalent linker represented by Formula V covalently linking the basic amino group to the nucleobase moiety:

wherein,

Q 1 and Q m are substituted or non-substituted methylene (—CH 2 —) radical, and Q m is directly linked to the basic amino group;

Q 2 , Q 3 , . . . , and Q m-1 are independently selected from substituted or non-substituted methylene or oxygen radical; and

m is an integer between 1 and 15.

2 . The peptide nucleic acid derivative according to claim 1 , or a pharmaceutical salt thereof:

wherein,

n is an integer between 11 and 19;

the compound of Formula I possesses at least a 10-mer complementary overlap with a 14-mer target splice site sequence that consists of 7-mer from intron and 7-mer from exon within a target pre-mRNA;

the compound of Formula I is fully complementary to the target pre-mRNA sequence;

S 1 , S 2 , . . . , S n-1 , S n , T 1 , T 2 , . . . , T n-1 , and T n are hydrido radical;

X is hydrido radical;

Y is substituted or non-substituted alkyloxycarbonyl radical;

Z is amino radical;

B 1 , B 2 , . . . , B n-1 , and B n are independently selected from adenine, thymine, guanine, cytosine, and unnatural nucleobases;

at least five of B 1 , B 2 , . . . , B n-1 , and B n are independently selected from unnatural nucleobases represented by Formula II, Formula III, or Formula IV;

R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrido radical;

L 1 represents —(CH 2 ) 2 —O—(CH 2 ) 2 —, —CH 2 —O—(CH 2 ) 2 —, —CH 2 —O—(CH 2 ) 3 —, —CH 2 —O—(CH 2 ) 4 —, —CH 2 —O—(CH 2 ) 5 —, —CH 2 —O—(CH 2 ) 6 —, or —CH 2 —O—(CH 2 ) 7 — with the right end is directly linked to the basic amino group; and

L 2 and L 3 are independently selected from —(CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 —, —(CH 2 ) 6 —, —(CH 2 ) 7 —, —(CH 2 ) 8 —, —(CH 2 ) 2 —O—(CH 2 ) 2 —, —(CH 2 ) 3 —O—(CH 2 ) 2 —, and —(CH 2 ) 2 —O—(CH 2 ) 3 — with the right end is directly linked to the basic amino group.

3 . The peptide nucleic acid derivative of claim 1 , wherein the target splice site sequence is not [(5′→3′) UAAGUAGGAUAAGU (SEQ ID NO: 5)] within the human HIF-1α pre-mRNA.

4 . A method of inducing in cells the skipping of the target exon within the target pre-mRNA comprising contacting the cells with the peptide nucleic acid derivative of claim 1 .

5 . A method of inducing in a subject the skipping of the target exon within the target pre-mRNA comprising administering the peptide nucleic acid derivative of claim 1 .

6 . A method of treating a disease or condition involving the expression of the target gene comprising administering the peptide nucleic acid derivative of claim 1 .

7 . A method of modulating in cells the functional activity of the target gene comprising contacting the cells with the peptide nucleic acid derivative of claim 1 .

8 . A method of modulating in a subject the functional activity of the target gene comprising administering the peptide nucleic acid derivative of claim 1 .

Assignments (1)

Continuity (2)

References Cited (107)