Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening

Aryamav Pattnaik; Nicholas Palermo; Bikash R Sahoo; Zhe Yuan; Duoyi Hu; Arun S Annamalai; Hiep L X Vu; Ignacio Correas; Pavan Kumar Prathipati; Christopher J Destache; Qingsheng Li; Fernando A Osorio; Asit K Pattnaik; Shi-Hua Xiang

doi:10.1016/j.antiviral.2017.12.016

Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening

Antiviral Res. 2018 Mar:151:78-86. doi: 10.1016/j.antiviral.2017.12.016. Epub 2017 Dec 21.

Authors

Affiliations

¹ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, USA.
² Holland Computing Center, University of Nebraska-Lincolns, USA.
³ School of Biological Sciences, University of Nebraska-Lincoln, USA.
⁴ Department of Animal Sciences, University of Nebraska-Lincoln, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
⁵ School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA.
⁶ School of Pharmacy and Health Professions, Creighton University, Omaha, NE 68178, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
⁷ School of Biological Sciences, University of Nebraska-Lincoln, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
⁸ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA.
⁹ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA. Electronic address: apattnaik2@unl.edu.
¹⁰ School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, USA; Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68583, USA. Electronic address: sxiang2@unl.edu.

PMID: 29274845
DOI: 10.1016/j.antiviral.2017.12.016

Abstract

Zika virus (ZIKV), an emerging arbovirus, has become a major human health concern globally due to its association with congenital abnormalities and neurological diseases. Licensed vaccines or antivirals against ZIKV are currently unavailable. Here, by employing a structure-based approach targeting the ZIKV RNA-dependent RNA polymerase (RdRp), we conducted in silico screening of a library of 100,000 small molecules and tested the top ten lead compounds for their ability to inhibit the virus replication in cell-based in vitro assays. One compound, 3-chloro-N-[({4-[4-(2-thienylcarbonyl)-1-piperazinyl]phenyl}amino)carbonothioyl]-1-benzothiophene-2-carboxamide (TPB), potently inhibited ZIKV replication at sub-micromolar concentrations. Molecular docking analysis suggests that TPB binds to the catalytic active site of the RdRp and therefore likely blocks the viral RNA synthesis by an allosteric effect. The IC₅₀ and the CC₅₀ of TPB in Vero cells were 94 nM and 19.4 μM, respectively, yielding a high selective index of 206. In in vivo studies using immunocompetent mice, TPB reduced ZIKV viremia significantly, indicating TPB as a potential drug candidate for ZIKV infections.

Keywords: In silico screening; Non-nucleoside inhibitor (NNI); RNA-dependent-RNA polymerase (RdRp); TPB; Zika virus (ZIKV).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antiviral Agents / chemistry
Antiviral Agents / metabolism
Antiviral Agents / pharmacology*
Cell Survival
Chlorocebus aethiops
Computer Simulation
Drug Discovery*
Enzyme Inhibitors / pharmacology*
Inhibitory Concentration 50
Mice, Inbred BALB C
Molecular Docking Simulation
RNA-Dependent RNA Polymerase / antagonists & inhibitors*
RNA-Dependent RNA Polymerase / chemistry
RNA-Dependent RNA Polymerase / metabolism
Small Molecule Libraries / chemistry
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology
Vero Cells
Viral Load / drug effects
Virus Replication / drug effects*
Zika Virus / drug effects*
Zika Virus / enzymology
Zika Virus / physiology
Zika Virus Infection / drug therapy
Zika Virus Infection / virology

Substances

Antiviral Agents
Enzyme Inhibitors
Small Molecule Libraries
RNA-Dependent RNA Polymerase