RNA interference and chemical modifications: Conformational and stereochemical aspects

CARB 7

Muthiah Manoharan, mmanoharan@alnylam.com, Drug Discovery, Alnylam Pharmaceuticals, 300 Third Street, Cambridge, MA 02142
A critical requirement for achieving safe and efficacious RNAi therapeutics is introduction of “drug-like” properties, such as stability, cellular delivery, and tissue bioavailability, into synthetic siRNAs to improve in vivo pharmacological properties. Recently we modified potential endo- and exonuclase cleavage sites by appropriate sugar and backbone modifications and improved in vivo serum and tissue half live of siRNA duplexes. These chemical changes enhanced in vivo stability and efficacy which led to potent siRNA compounds. These results represent a significant advance in the development of siRNA therapeutics via appropriate chemical modifications and could be explained from the stereochemical and conformational features of chemically modified nucleotides.