Identification of Small Molecule Inhibitors of RNase L by Fragment-Based Drug Discovery

The pseudokinase-endoribonuclease
RNase L plays important roles
in antiviral innate immunity and is also implicated in many other
cellular activities. The inhibition of RNase L showed therapeutic
potential for Aicardi-Goutières syndrome (AGS). Thus, RNase
L is a promising drug target. In this study, using an enzyme assay
and NMR screening, we discovered 13 inhibitory fragments against RNase
L. Cocrystal structures of RNase L separately complexed with two different
fragments were determined in which both fragments bound to the ATP-binding
pocket of the pseudokinase domain. Myricetin, vitexin, and hyperoside,
three natural products sharing similar scaffolds with the fragment
AC40357, demonstrated a potent inhibitory activity in vitro. In addition, myricetin has a promising cellular inhibitory activity.
A cocrystal structure of RNase L with myricetin provided a structural
basis for inhibitor design by allosterically modulating the ribonuclease
activity. Our findings demonstrate that fragment screening can lead
to the discovery of natural product inhibitors of RNase L.