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Article: The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

TitleThe celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy
Authors
KeywordsAR-12
Antiviral
Flavivirus
Inhibitor
Kinase
Zika
Issue Date2018
Citation
Antiviral Research, 2018, v. 160, p. 38-47 How to Cite?
Abstract© 2018 Elsevier B.V. Zika virus (ZIKV) is a human-pathogenic flavivirus that has recently emerged as a global public health threat. ZIKV infection may be associated with congenital malformations in infected fetuses and severe neurological and systemic complications in infected adults. There are currently limited treatment options for ZIKV infection. AR-12 (OSU-03012) is a celecoxib derivative cellular kinase inhibitor that has broad-spectrum antiviral activities. In this study, we investigated the antiviral activity and mechanism of AR-12 against ZIKV. We evaluated the in vitro anti-ZIKV activity of AR-12, using cell protection and virus yield reduction assays, in multiple clinically relevant cell lines, and the in vivo treatment effects of AR-12 in a lethal mouse model using type I interferon receptor-deficient A129 mice. AR-12 inhibited ZIKV strains belonging to both the African and Asian/American lineages in Huh-7 and/or neuronal cells. AR12's IC50 against ZIKV was consistently <2 μM in these cells. ZIKV-infected A129 mice treated with intraperitoneally or orally administered AR-12 had significantly higher survival rate (50.0%–83.3% vs 0%, P < 0.05), less body weight loss, and lower blood and tissue ZIKV RNA loads than untreated control A129 mice. These anti-ZIKV effects were likely the results of down-regulation of the PI3K/Akt pathway by AR-12. Clinical trials using the clinically available and broad-spectrum AR-12 as an empirical treatment should be considered especially for patients residing in or returning from areas endemic of ZIKV and other arboviral infections who present with an acute undifferentiated febrile illness.
Persistent Identifierhttp://hdl.handle.net/10722/280688
ISSN
2023 Impact Factor: 4.5
2023 SCImago Journal Rankings: 1.500
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorChan, Jasper Fuk Woo-
dc.contributor.authorZhu, Zheng-
dc.contributor.authorChu, Hin-
dc.contributor.authorYuan, Shuofeng-
dc.contributor.authorChik, Kenn Ka Heng-
dc.contributor.authorChan, Chris Chung Sing-
dc.contributor.authorPoon, Vincent Kwok Man-
dc.contributor.authorYip, Cyril Chik Yan-
dc.contributor.authorZhang, Xi-
dc.contributor.authorTsang, Jessica Oi Ling-
dc.contributor.authorZou, Zijiao-
dc.contributor.authorTee, Kah Meng-
dc.contributor.authorShuai, Huiping-
dc.contributor.authorLu, Gang-
dc.contributor.authorYuen, Kwok Yung-
dc.date.accessioned2020-02-17T14:34:41Z-
dc.date.available2020-02-17T14:34:41Z-
dc.date.issued2018-
dc.identifier.citationAntiviral Research, 2018, v. 160, p. 38-47-
dc.identifier.issn0166-3542-
dc.identifier.urihttp://hdl.handle.net/10722/280688-
dc.description.abstract© 2018 Elsevier B.V. Zika virus (ZIKV) is a human-pathogenic flavivirus that has recently emerged as a global public health threat. ZIKV infection may be associated with congenital malformations in infected fetuses and severe neurological and systemic complications in infected adults. There are currently limited treatment options for ZIKV infection. AR-12 (OSU-03012) is a celecoxib derivative cellular kinase inhibitor that has broad-spectrum antiviral activities. In this study, we investigated the antiviral activity and mechanism of AR-12 against ZIKV. We evaluated the in vitro anti-ZIKV activity of AR-12, using cell protection and virus yield reduction assays, in multiple clinically relevant cell lines, and the in vivo treatment effects of AR-12 in a lethal mouse model using type I interferon receptor-deficient A129 mice. AR-12 inhibited ZIKV strains belonging to both the African and Asian/American lineages in Huh-7 and/or neuronal cells. AR12's IC50 against ZIKV was consistently <2 μM in these cells. ZIKV-infected A129 mice treated with intraperitoneally or orally administered AR-12 had significantly higher survival rate (50.0%–83.3% vs 0%, P < 0.05), less body weight loss, and lower blood and tissue ZIKV RNA loads than untreated control A129 mice. These anti-ZIKV effects were likely the results of down-regulation of the PI3K/Akt pathway by AR-12. Clinical trials using the clinically available and broad-spectrum AR-12 as an empirical treatment should be considered especially for patients residing in or returning from areas endemic of ZIKV and other arboviral infections who present with an acute undifferentiated febrile illness.-
dc.languageeng-
dc.relation.ispartofAntiviral Research-
dc.subjectAR-12-
dc.subjectAntiviral-
dc.subjectFlavivirus-
dc.subjectInhibitor-
dc.subjectKinase-
dc.subjectZika-
dc.titleThe celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.antiviral.2018.10.007-
dc.identifier.pmid30326204-
dc.identifier.pmcidPMC7113887-
dc.identifier.scopuseid_2-s2.0-85055254013-
dc.identifier.hkuros331496-
dc.identifier.volume160-
dc.identifier.spage38-
dc.identifier.epage47-
dc.identifier.eissn1872-9096-
dc.identifier.isiWOS:000451936000005-
dc.identifier.issnl0166-3542-

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