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 Vu, Ignacio Correas, Pavan Kumar Prathipati, Christopher J. Destache, Qingsheng Li, Fernando A. Osorio, Asit K Pattnaik, Shi-Hua Xiang

Research output: Contribution to journalArticle

7 Citations (Scopus)

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 IC 50 and the CC 50 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.

Original languageEnglish (US)
Pages (from-to)78-86
Number of pages9
JournalAntiviral Research
Volume151
DOIs
StatePublished - Mar 2018

Fingerprint

DNA-Directed RNA Polymerases
Virus Replication
Computer Simulation
RNA Replicase
Catalytic Domain
Molecular Docking Simulation
Arboviruses
Vero Cells
Viremia
Viral RNA
Libraries
Antiviral Agents
Vaccines
Zika Virus
Health
Pharmaceutical Preparations

Keywords

  • In silico screening
  • Non-nucleoside inhibitor (NNI)
  • RNA-dependent-RNA polymerase (RdRp)
  • TPB
  • Zika virus (ZIKV)

ASJC Scopus subject areas

  • Pharmacology
  • Virology

Cite this

Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening. / Pattnaik, Aryamav; Palermo, Nicholas; Sahoo, Bikash R.; Yuan, Zhe; Hu, Duoyi; Annamalai, Arun S.; Vu, Hiep L; Correas, Ignacio; Prathipati, Pavan Kumar; Destache, Christopher J.; Li, Qingsheng; Osorio, Fernando A.; Pattnaik, Asit K; Xiang, Shi-Hua.

In: Antiviral Research, Vol. 151, 03.2018, p. 78-86.

Research output: Contribution to journalArticle

Pattnaik, A, Palermo, N, Sahoo, BR, Yuan, Z, Hu, D, Annamalai, AS, Vu, HL, Correas, I, Prathipati, PK, Destache, CJ, Li, Q, Osorio, FA, Pattnaik, AK & Xiang, S-H 2018, 'Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening', Antiviral Research, vol. 151, pp. 78-86. https://doi.org/10.1016/j.antiviral.2017.12.016
Pattnaik, Aryamav ; Palermo, Nicholas ; Sahoo, Bikash R. ; Yuan, Zhe ; Hu, Duoyi ; Annamalai, Arun S. ; Vu, Hiep L ; Correas, Ignacio ; Prathipati, Pavan Kumar ; Destache, Christopher J. ; Li, Qingsheng ; Osorio, Fernando A. ; Pattnaik, Asit K ; Xiang, Shi-Hua. / Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening. In: Antiviral Research. 2018 ; Vol. 151. pp. 78-86.
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AU - Vu, Hiep L

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AU - Prathipati, Pavan Kumar

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