Silencing activity of 2′-O-methyl modified anti-MDR1 siRNAs with mismatches in the central part of the duplexes

► siRNAs destabilized by mismatches introduced to the central part of the duplex. ► Selective protection of nuclease-sensitive sites in siRNA by 2′-O-methyl analogs. ► Wobble pairs are better tolerated by RNAi machinery than mismatches. ► GU wobble pairs in the central part of the duplex can enhance silencing activity.