Probing RNA interference with nonpolar isosteres

ORGN 672

Alvaro Somoza, alvaros@stanford.edu, Jijumon Chelliserrykattil, and Eric T. Kool, kool@stanford.edu. Department of Chemistry, Stanford University, 333 Campus Drive 121, Mail box 44, Stanford, CA 94305
RNA interference has become an essential tool in biological and biomedical research to study gene function, by specifically silencing a targeted gene. Moreover, it is also considered a potential therapeutic strategy for genetic therapy. Despite the mechanistic studies carried out in this area, it is not known whether base pair selectivity arises from base complementary or from other factors, such as sterics, dictated by an enforced environment inside of the RISC complex. This presentation will address this issue by using a nonpolar shape mimic of uracil (namely, difluorobenzene) as probe to study the importance of sterics and hydrogen bonding in RNA interference. Our results suggest, surprisingly, that Watson-Crick hydrogen bonding is not necessary at all positions for biological activity.