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- Publisher Website: 10.1016/j.antiviral.2017.07.007
- Scopus: eid_2-s2.0-85025077533
- PMID: 28712942
- WOS: WOS:000411547700006
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Article: Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo
Title | Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo |
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Authors | |
Keywords | Zika Flavivirus Novobiocin Protease Treatment Molecular modelling |
Issue Date | 2017 |
Publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral |
Citation | Antiviral Research, 2017, v. 145, p. 33-43 How to Cite? |
Abstract | Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. |
Persistent Identifier | http://hdl.handle.net/10722/246094 |
ISSN | 2021 Impact Factor: 10.103 2020 SCImago Journal Rankings: 2.052 |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Yuan, S | - |
dc.contributor.author | Chan, JFW | - |
dc.contributor.author | den-Haan, H | - |
dc.contributor.author | Chik, KKH | - |
dc.contributor.author | Zhang, AJ | - |
dc.contributor.author | Chan, CCS | - |
dc.contributor.author | Poon, VKM | - |
dc.contributor.author | Yip, CCY | - |
dc.contributor.author | Mak, WWN | - |
dc.contributor.author | Zhu, Z | - |
dc.contributor.author | Zou, Z | - |
dc.contributor.author | Tee, KM | - |
dc.contributor.author | Cai, J | - |
dc.contributor.author | Chan, KH | - |
dc.contributor.author | de la Peña, J | - |
dc.contributor.author | Pérez-Sánchez, H | - |
dc.contributor.author | Cerón-Carrasco, JP | - |
dc.contributor.author | Yuen, KY | - |
dc.date.accessioned | 2017-09-18T02:22:18Z | - |
dc.date.available | 2017-09-18T02:22:18Z | - |
dc.date.issued | 2017 | - |
dc.identifier.citation | Antiviral Research, 2017, v. 145, p. 33-43 | - |
dc.identifier.issn | 0166-3542 | - |
dc.identifier.uri | http://hdl.handle.net/10722/246094 | - |
dc.description.abstract | Zika virus (ZIKV) infection may be associated with severe complications in fetuses and adults, but treatment options are limited. We performed an in silico structure-based screening of a large chemical library to identify potential ZIKV NS2B-NS3 protease inhibitors. Clinically approved drugs belonging to different drug classes were selected among the 100 primary hit compounds with the highest predicted binding affinities to ZIKV NS2B-NS3-protease for validation studies. ZIKV NS2B-NS3 protease inhibitory activity was validated in most of the selected drugs and in vitro anti-ZIKV activity was identified in two of them (novobiocin and lopinavir-ritonavir). Molecular docking and molecular dynamics simulations predicted that novobiocin bound to ZIKV NS2B-NS3-protease with high stability. Dexamethasone-immunosuppressed mice with disseminated ZIKV infection and novobiocin treatment had significantly (P < 0.05) higher survival rate (100% vs 0%), lower mean blood and tissue viral loads, and less severe histopathological changes than untreated controls. This structure-based drug discovery platform should facilitate the identification of additional enzyme inhibitors of ZIKV. | - |
dc.language | eng | - |
dc.publisher | Elsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral | - |
dc.relation.ispartof | Antiviral Research | - |
dc.subject | Zika | - |
dc.subject | Flavivirus | - |
dc.subject | Novobiocin | - |
dc.subject | Protease | - |
dc.subject | Treatment | - |
dc.subject | Molecular modelling | - |
dc.title | Structure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo | - |
dc.type | Article | - |
dc.identifier.email | Yuan, S: yuansf@hku.hk | - |
dc.identifier.email | Chan, JFW: jfwchan@hku.hk | - |
dc.identifier.email | Zhang, AJ: zhangajx@hkucc.hku.hk | - |
dc.identifier.email | Chan, CCS: cschan@hkucc.hku.hk | - |
dc.identifier.email | Poon, VKM: vinpoon@hku.hk | - |
dc.identifier.email | Yip, CCY: yipcyril@hku.hk | - |
dc.identifier.email | Tee, KM: tkahmeng@hku.hk | - |
dc.identifier.email | Cai, J: caijuice@hku.hk | - |
dc.identifier.email | Chan, KH: chankh2@hkucc.hku.hk | - |
dc.identifier.email | Yuen, KY: kyyuen@hkucc.hku.hk | - |
dc.identifier.authority | Yuan, S=rp02640 | - |
dc.identifier.authority | Chan, JFW=rp01736 | - |
dc.identifier.authority | Zhang, AJ=rp00413 | - |
dc.identifier.authority | Yip, CCY=rp01721 | - |
dc.identifier.authority | Chan, KH=rp01921 | - |
dc.identifier.authority | Yuen, KY=rp00366 | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1016/j.antiviral.2017.07.007 | - |
dc.identifier.pmid | 28712942 | - |
dc.identifier.scopus | eid_2-s2.0-85025077533 | - |
dc.identifier.hkuros | 276537 | - |
dc.identifier.volume | 145 | - |
dc.identifier.spage | 33 | - |
dc.identifier.epage | 43 | - |
dc.identifier.isi | WOS:000411547700006 | - |
dc.publisher.place | Netherlands | - |
dc.identifier.issnl | 0166-3542 | - |