Key result
PPNDS inhibited murine Norovirus RNA-dependent RNA-polymerase in vitro with a low micromolar IC50 by mimicking two stacked nucleotide bases to block RNA exit.
PPNDS inhibits murine norovirus RdRp by mimicking two stacked nucleotide bases, providing a structural basis for potential antiviral development.
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Offers template for norovirus RdRp inhibitors; leaves open in vivo efficacy and clinical translation.
Norovirus (NV) is a major cause of gastroenteritis worldwide. Antivirals against such important pathogens are on demand. Among the viral proteins that orchestrate viral replication, RNA-dependent-RNA-polymerase (RdRp) is a promising drug development target. From an in silico-docking search focused on the RdRp active site, we selected the compound PPNDS, which showed low micromolar IC50vs. murine NV-RdRp in vitro. We report the crystal structure of the murine NV-RdRp/PPNDS complex showing that two molecules of the inhibitor bind in antiparallel stacking interaction, properly oriented to block exit of the newly synthesized RNA. Such inhibitor-binding mode mimics two stacked nucleotide-bases of the RdRp/ssRNA complex.
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Croci et al. (2014) studied Norovirus infection (in vitro). PPNDS was evaluated on IC50 vs. murine NV-RdRp in vitro and crystal structure binding mode. PPNDS inhibited murine Norovirus RNA-dependent RNA-polymerase in vitro with a low micromolar IC50 by mimicking two stacked nucleotide bases to block RNA exit.
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