PPNDS inhibits murine Norovirus RNA-dependent RNA-polymerase mimicking two RNA stacking bases

被引：23

作者：

Croci, Romina ^{[1
]}

Tarantino, Delia ^{[1
]}

Milani, Mario ^{[1
,2
]}

Pezzullo, Margherita ^{[1
,2
]}

Rohayem, Jacques ^{[3
,4
]}

Bolognesi, Martino ^{[1
]}

Mastrangelo, Eloise ^{[1
,2
]}

机构：

[1] Univ Milan, Dept Biosci, I-20133 Milan, Italy

[2] CNR IBF, Ist Biofis, I-20133 Milan, Italy

[3] Tech Univ Dresden, Inst Virol, D-01307 Dresden, Germany

[4] Riboxx GmbH, Pharmapk Radebeul, D-01445 Radebeul, Germany

来源：

FEBS LETTERS | 2014年 / 588卷 / 09期

关键词：

Norovirus; RNA-dependent-RNA-polymerase; Antiviral discovery; In silico-docking; X-ray crystallography; PPNDS; SURAMIN; POLYPROTEIN;

D O I：

10.1016/j.febslet.2014.03.021

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 IC50 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. (C) 2014 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

引用

页码：1720 / 1725

页数：6

共 33 条

[1] Electrostatics of nanosystems: Application to microtubules and the ribosome [J].