Identification of Small-Molecule Inhibitors for Enterovirus A71 IRES by Structure-Based Virtual Screening

Structured
RNAs play a crucial role in regulating gene expression,
which includes both protein synthesis and RNA processing. Dysregulation
of these processes is associated with various conditions, including
viral and bacterial infections, as well as cancer. The unique tertiary
structures of structured RNAs provide an opportunity for small molecules
to directly modulate such processes, making them promising targets
for drug discovery. Although small-molecule inhibitors targeting RNA
have shown early success, in silico strategies like
structure-based virtual screening remain underutilized for RNA-targeted
drug discovery. In this study, we developed a virtual screening scheme
targeting the structural ensemble of EV-A71 IRES SL II, a noncoding
viral RNA element essential for viral replication. We subsequently
optimized the experimentally validated hit compound IRE-03 from virtual
screening through an “analog-by-catalog” search. This
led to the identification of a more potent IRES inhibitor, IRE-03-3,
validated through biochemical and functional assays with an EC50 value of 11.96 μM against viral proliferation. Our
findings demonstrate that structure-based virtual screening can be
effectively applied to RNA targets, providing exciting new opportunities
for future antiviral drug discovery.