2020 EJRNL PP Jeong Yong Choe -1.pdf
Terbatas Irwan Sofiyan
» ITB
Terbatas Irwan Sofiyan
» ITB
The efficient delivery of small interfering RNAs
(siRNAs) to the target cells is critical for the pharmaceutical
success of RNA interference (RNAi) drugs. One of the possible
strategies to improve siRNA delivery is to identify auxiliary
molecules that augment their cellular uptake. Herein, we performed
a chemical library screening in an effort to discover small molecules
that enhance the potency of cholesterol-conjugated, cell-penetrating
asymmetric siRNAs (cp-asiRNAs). Interestingly, three
compounds identified from the screen share a common
dihydropyridine (DHP) core and function as L-type calcium
channel blockers (CCBs). Using confocal microscopy and
quantitative analysis of small RNAs, we demonstrated that the L-type CCBs increased the endocytic cellular uptake of cpasiRNAs. Furthermore, these small molecules substantially improved the potency of cp-asiRNAs, not only in vitro but also in vivo on rat skin. Collectively, our study provides an alternative pharmacological approach for the identification of small molecules that potentiate the effects of therapeutic siRNAs.