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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

TitleStructure-based discovery of clinically approved drugs as Zika virus NS2B-NS3 protease inhibitors that potently inhibit Zika virus infection in vitro and in vivo
Authors
KeywordsZika
Flavivirus
Novobiocin
Protease
Treatment
Molecular modelling
Issue Date2017
PublisherElsevier 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?
AbstractZika 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 Identifierhttp://hdl.handle.net/10722/246094
ISSN
2019 Impact Factor: 4.101
2015 SCImago Journal Rankings: 2.080
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYuan, S-
dc.contributor.authorChan, JFW-
dc.contributor.authorden-Haan, H-
dc.contributor.authorChik, KKH-
dc.contributor.authorZhang, AJ-
dc.contributor.authorChan, CCS-
dc.contributor.authorPoon, VKM-
dc.contributor.authorYip, CCY-
dc.contributor.authorMak, WWN-
dc.contributor.authorZhu, Z-
dc.contributor.authorZou, Z-
dc.contributor.authorTee, KM-
dc.contributor.authorCai, J-
dc.contributor.authorChan, KH-
dc.contributor.authorde la Peña, J-
dc.contributor.authorPérez-Sánchez, H-
dc.contributor.authorCerón-Carrasco, JP-
dc.contributor.authorYuen, KY-
dc.date.accessioned2017-09-18T02:22:18Z-
dc.date.available2017-09-18T02:22:18Z-
dc.date.issued2017-
dc.identifier.citationAntiviral Research, 2017, v. 145, p. 33-43-
dc.identifier.issn0166-3542-
dc.identifier.urihttp://hdl.handle.net/10722/246094-
dc.description.abstractZika 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.languageeng-
dc.publisherElsevier BV. The Journal's web site is located at http://www.elsevier.com/locate/antiviral-
dc.relation.ispartofAntiviral Research-
dc.subjectZika-
dc.subjectFlavivirus-
dc.subjectNovobiocin-
dc.subjectProtease-
dc.subjectTreatment-
dc.subjectMolecular modelling-
dc.titleStructure-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.typeArticle-
dc.identifier.emailYuan, S: yuansf@hku.hk-
dc.identifier.emailChan, JFW: jfwchan@hku.hk-
dc.identifier.emailZhang, AJ: zhangajx@hkucc.hku.hk-
dc.identifier.emailChan, CCS: cschan@hkucc.hku.hk-
dc.identifier.emailPoon, VKM: vinpoon@hku.hk-
dc.identifier.emailYip, CCY: yipcyril@hku.hk-
dc.identifier.emailTee, KM: tkahmeng@hku.hk-
dc.identifier.emailCai, J: caijuice@hku.hk-
dc.identifier.emailChan, KH: chankh2@hkucc.hku.hk-
dc.identifier.emailYuen, KY: kyyuen@hkucc.hku.hk-
dc.identifier.authorityYuan, S=rp02640-
dc.identifier.authorityChan, JFW=rp01736-
dc.identifier.authorityZhang, AJ=rp00413-
dc.identifier.authorityYip, CCY=rp01721-
dc.identifier.authorityChan, KH=rp01921-
dc.identifier.authorityYuen, KY=rp00366-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.antiviral.2017.07.007-
dc.identifier.pmid28712942-
dc.identifier.scopuseid_2-s2.0-85025077533-
dc.identifier.hkuros276537-
dc.identifier.volume145-
dc.identifier.spage33-
dc.identifier.epage43-
dc.identifier.isiWOS:000411547700006-
dc.publisher.placeNetherlands-
dc.identifier.issnl0166-3542-

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