Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/80153
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dc.contributor.authorPhoo, Wint Winten
dc.contributor.authorZhang, Zhenzhenen
dc.contributor.authorWirawan, Melissaen
dc.contributor.authorChew, Edwin Jun Chenen
dc.contributor.authorChew, Alvin Bing Liangen
dc.contributor.authorKouretova, Jennyen
dc.contributor.authorSteinmetzer, Torstenen
dc.contributor.authorLuo, Dahaien
dc.date.accessioned2019-11-07T05:09:08Zen
dc.date.accessioned2019-12-06T13:41:45Z-
dc.date.available2019-11-07T05:09:08Zen
dc.date.available2019-12-06T13:41:45Z-
dc.date.issued2018en
dc.identifier.citationPhoo, W. W., Zhang, Z., Wirawan, M., Chew, E. J. C., Chew, A. B. L., Kouretova, J., . . . Luo, D. (2018). Structures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitors. Antiviral Research, 160, 17-24. doi:10.1016/j.antiviral.2018.10.006en
dc.identifier.issn0166-3542en
dc.identifier.urihttps://hdl.handle.net/10356/80153-
dc.identifier.urihttp://hdl.handle.net/10220/50366en
dc.description.abstractZika virus NS2B-NS3 protease plays an essential role in viral replication by processing the viral polyprotein into individual proteins. The viral protease is therefore considered as an ideal antiviral drug target. To facilitate the development of protease inhibitors, we report three high-resolution co-crystal structures of bZiPro with peptidomimetic inhibitors composed of a P1-P4 segment and different P1′ residues. Compounds 1 and 2 possess small P1′ groups that are split off by bZiPro, which could be detected by mass spectrometry. On the other hand, the more potent compound 3 contains a bulky P1′ benzylamide structure that is resistant to cleavage by bZiPro, demonstrating that presence of an uncleavable C-terminal cap contributes to a slightly improved inhibitory potency. The N-terminal phenylacetyl residue occupies a position above the P1 side chain and therefore stabilizes a horseshoe-like backbone conformation of the bound inhibitors. The P4 moieties show unique intra- and intermolecular interactions. Our work reports the detailed binding mode interactions of substrate-analogue inhibitors within the S4-S1′ pockets and explains the preference of bZiPro for basic P1-P3 residues. These new structures of protease-inhibitor complexes will guide the design of more effective NS2B-NS3 protease inhibitors with improved potency and bioavailability.en
dc.description.sponsorshipNRF (Natl Research Foundation, S’pore)en
dc.description.sponsorshipMOE (Min. of Education, S’pore)en
dc.description.sponsorshipNMRC (Natl Medical Research Council, S’pore)en
dc.format.extent26 p.en
dc.language.isoenen
dc.relation.ispartofseriesAntiviral Researchen
dc.rights© 2018 Elsevier B.V. All rights reserved. This paper was published in Antiviral Research and is made available with permission of Elsevier B.V.en
dc.subjectScience::Medicineen
dc.subjectNS3 Proteaseen
dc.subjectZika Virusen
dc.titleStructures of Zika virus NS2B-NS3 protease in complex with peptidomimetic inhibitorsen
dc.typeJournal Articleen
dc.contributor.schoolSchool of Biological Sciencesen
dc.contributor.schoolInterdisciplinary Graduate School (IGS)en
dc.contributor.schoolLee Kong Chian School of Medicine (LKCMedicine)en
dc.contributor.organizationInstitute of Structural Biologyen
dc.contributor.organizationInstitute of Health Technologiesen
dc.identifier.doihttp://dx.doi.org/10.1016/j.antiviral.2018.10.006en
dc.description.versionAccepted versionen
item.grantfulltextopen-
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Appears in Collections:IGS Journal Articles
LKCMedicine Journal Articles
SBS Journal Articles

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