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dc.contributor.authorRassias, Gerasimos
dc.contributor.authorZogali, Vasiliki
dc.contributor.authorSwarbrick, Crystall MD
dc.contributor.authorChan, Kitti Wing Ki
dc.contributor.authorChan, Shu Ann
dc.contributor.authorGwee, Chin Piaw
dc.contributor.authorWang, Sai
dc.contributor.authorKaplanai, Entzy
dc.contributor.authorCanko, Aleksander
dc.contributor.authorKiousis, Dimitrios
dc.contributor.authorLescar, Julien
dc.contributor.authorLuo, Dahai
dc.contributor.authorMatsoukas, Minos-Timotheos
dc.contributor.authorVasudevan, Subhash G
dc.date.accessioned2019-08-26T06:18:17Z
dc.date.available2019-08-26T06:18:17Z
dc.date.issued2019
dc.identifier.issn0223-5234
dc.identifier.doi10.1016/j.ejmech.2019.07.007
dc.identifier.urihttp://hdl.handle.net/10072/386688
dc.description.abstractZika virus (ZIKV) infection recently resulted in an international health emergency the Americas in and despite its high profile there is currently no approved treatment for ZIKV infection with millions of people being at risk. ZIKV is a member of Flaviviridae family which includes prominent members such as dengue virus (DENV) and West Nile virus (WNV). One of the best validated targets for developing anti-flaviviral treatment for DENV and WNV infection is the NS2B/NS3 protease. However the inhibitors reported to date have shown limited promise for further clinical development largely due to poor cellular activity. Prompted by the conserved nature of the viral NS2B/NS3 protease across flaviviruses, we envisaged that small molecule inhibitors of the ZIKVpro may be developed by applying rational design on previously reported scaffolds with demonstrated activity against other flaviviral proteases. Starting with an earlier WNVpro hit we performed a scaffold hopping exercise and discovered that certain carbazole derivatives bearing amidine groups possessed submicromolar potency and significant cellular activity against ZIKV. We successfully addressed various issues with the synthesis of novel N-substituted carbazole-based amidines thus permitting a targeted SAR campaign. The in vitro biochemical and cell-based inhibitory profiles exhibited by the lead molecule described in this work (ZIKVpro IC50 0.52 μM, EC50 1.25 μM), is among the best reported to date. Furthermore, these molecules possess capacity for further optimization of pharmacokinetics and may evolve to broad spectrum flaviviral protease inhibitors.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherElsevier
dc.relation.ispartofpagefrom536
dc.relation.ispartofpageto545
dc.relation.ispartofjournalEuropean Journal of Medicinal Chemistry
dc.relation.ispartofvolume180
dc.subject.fieldofresearchMedicinal and Biomolecular Chemistry
dc.subject.fieldofresearchOrganic Chemistry
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode0304
dc.subject.fieldofresearchcode0305
dc.subject.fieldofresearchcode1115
dc.subject.keywordsAmidines
dc.subject.keywordsCarbazoles
dc.subject.keywordsFlavivirus
dc.subject.keywordsInhibitors
dc.subject.keywordsProtease
dc.titleCell-active carbazole derivatives as inhibitors of the zika virus protease.
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationRassias, G; Zogali, V; Swarbrick, CMD; Ki Chan, KW; Chan, SA; Gwee, CP; Wang, S; Kaplanai, E; Canko, A; Kiousis, D; Lescar, J; Luo, D; Matsoukas, M-T; Vasudevan, SG, Cell-active carbazole derivatives as inhibitors of the zika virus protease., European Journal of Medicinal Chemistry, 2019, 180, pp. 536-545
dcterms.dateAccepted2019-07-02
dcterms.licensehttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated2019-08-26T06:10:46Z
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2019 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorSwarbrick, Crystall
gro.griffith.authorVasudevan, Subhash


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