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PPNDS inhibits murine Norovirus RNA‐dependent RNA‐polymerase mimicking two RNA stacking bases
Author(s) -
Croci Romina,
Tarantino Delia,
Milani Mario,
Pezzullo Margherita,
Rohayem Jacques,
Bolognesi Martino,
Mastrangelo Eloise
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.03.021
Subject(s) - rna polymerase , rna , rna dependent rna polymerase , polymerase , norovirus , in silico , virology , biology , chemistry , microbiology and biotechnology , genetics , enzyme , biochemistry , virus , gene
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 IC 50 vs . 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.