THERAPEUTIC OLIGONUCLEOTIDES COMPRISING PYRAZOLOTRIAZINE NUCLEOTIDE ANALOGUES

摘要

Disclosed herein are double-stranded RNA nucleic acid molecules, which include at least one pyrazolotriazine nucleotide analogue and have been modified to exhibit one of the following, increased on-target activity, increased target specificity, enhanced nuclease stability, reduced off target activity and/or reduced immunogenicity when compared to an unmodified or similarly modified dsRNA; pharmaceutical compositions comprising such molecules and methods of use thereof in therapy.

主权项

1. A double-stranded nucleic acid molecule having the following general structure A1:
5′ (N)x-Z 3′ (antisense strand) 3′ Z′—(N′)y-z″ 5′ (sense strand)  (A1) wherein each of N and N′ is an unmodified ribonucleotide, a modified ribonucleotide, or an unconventional moiety, and at least one of N or N′ comprises a pyrazolotriazine (PT) nucleotide analogue; wherein each of (N)x and (N′)y is an oligonucleotide in which each consecutive N or N′ is joined to the next N or N′ by a covalent bond; wherein each of Z and Z′ is independently present or absent, but if present independently includes 1-5 consecutive nucleotides, PT nucleotide analogues or non-nucleotide moieties or a combination thereof, or a vitamin, or a drug moiety, covalently attached at the 3′ terminus of the strand in which it is present; wherein z″ may be present or absent, but if present is a capping moiety covalently attached at the 5′ terminus of (N′)y; wherein each of x and y is independently an integer between 15 and 40; and wherein the sequence of (N′)y is complementary to the sequence of (N)x and wherein at least a portion of the sequence of (N)x is complementary to a consecutive sequence in a target RNA; with the proviso that not each N and N′ is a deoxyribonucleotide.