Rational design of prodrug-type apoB-targeted siRNA for nuclease resistance improvement without compromising gene silencing potency

In this study, we developed a nuclease-resistant prodrug-type 2'-O-MDTM siRNA for deployment in future animal experiments. To rationally design siRNA modified with a minimal number of 2'-O-MDTM nucleotide residues, we identified the sites susceptible to nuclease digestion and tolerant to 2'-O-methyl (2'-OMe) modification in the antisense strand of apolipoprotein B-targeted siRNA. Subsequently, we optimized the positions where the 2'-OMe and 2'-O-MDTM groups should be incorporated. siRNA bearing the 2'-O-MDTM and 2'-OMe groups at their respective optimized positions exhibited efficient knockdown potency in vitro and enhanced stability in serum.PMID:38552598 | DOI:10.1016/j.bmc.2024.117693
Source: Bioorganic and Medicinal Chemistry - Category: Chemistry Authors: Source Type: research