MicroRNAs (
miRNAs) are short noncoding RNAs, which bind to messenger RNAs and regulate
protein expression. The biosynthesis of
miRNAs includes two precursors, a
primary miRNA transcript (
pri-miRNA) and a shorter
pre-miRNA, both of which carry a common stem-loop bearing the mature
miRNA. MiR-122 is a liver-specific
miRNA with an important role in the life cycle of hepatitis C virus (HCV). It is the target of
miravirsen (
SPC3649), an antimiR
drug candidate currently in clinical testing for treatment of HCV
infections.
Miravirsen is composed of
locked nucleic acid (LNAs)
ribonucleotides interspaced throughout
a DNA phosphorothioate sequence complementary to mature miR-122. The LNA modifications endow the
drug with high affinity for its target and provide resistance to nuclease degradation. While
miravirsen is thought to work mainly by hybridizing to mature miR-122 and blocking its interaction with HCV
RNA, its target sequence is also present in pri- and pre-miR-122. Using new in vitro and cellular assays specifically developed to discover
ligands that suppress biogenesis of miR-122, we show that
miravirsen binds to the stem-loop structure of pri- and pre-miR-122 with nanomolar affinity, and inhibits both Dicer- and Drosha-mediated processing of miR-122 precursors. This inhibition may contribute to the pharmacological activity of the
drug in man.