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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 78-86 |
| Number of pages | 9 |
| Journal | Antiviral Research |
| Volume | 151 |
| DOIs | |
| State | Published - Mar 1 2018 |
Fingerprint
All Science Journal Classification (ASJC) codes
- 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.X.; Correas, Ignacio; Prathipati, Pavan Kumar; Destache, Christopher J.; Li, Qingsheng; Osorio, Fernando A.; Pattnaik, Asit K.; Xiang, Shi hua.
In: Antiviral Research, Vol. 151, 01.03.2018, p. 78-86.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Discovery of a non-nucleoside RNA polymerase inhibitor for blocking Zika virus replication through in silico screening
AU - Pattnaik, Aryamav
AU - Palermo, Nicholas
AU - Sahoo, Bikash R.
AU - Yuan, Zhe
AU - Hu, Duoyi
AU - Annamalai, Arun S.
AU - Vu, Hiep L.X.
AU - Correas, Ignacio
AU - Prathipati, Pavan Kumar
AU - Destache, Christopher J.
AU - Li, Qingsheng
AU - Osorio, Fernando A.
AU - Pattnaik, Asit K.
AU - Xiang, Shi hua
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85041690189&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041690189&partnerID=8YFLogxK
U2 - 10.1016/j.antiviral.2017.12.016
DO - 10.1016/j.antiviral.2017.12.016
M3 - Article
VL - 151
SP - 78
EP - 86
JO - Antiviral Research
JF - Antiviral Research
SN - 0166-3542
ER -