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dc.contributor.authorTyndall, Joel
dc.contributor.authorHuston, Wilhelmina
dc.contributor.authorGamble, Allan
dc.contributor.authorMcCaughey, Laura
dc.contributor.authorMarsh, James
dc.contributor.authorSpringwald, Alexandra
dc.contributor.authorMazraani, Rami
dc.contributor.authorPeel, Emma
dc.contributor.authorHwang, Jimin
dc.contributor.authorAgbowuro, Ayodeji
dc.date.available2021-08-29T21:44:19Z
dc.date.copyright2019-09
dc.identifier.citationTyndall, J., Huston, W., Gamble, A., McCaughey, L., Marsh, J., Springwald, A., … Agbowuro, A. (2019). Structure-Activity Analysis of Peptidic Chlamydia HtrA Inhibitors. Bioorg Med Chem, 27(10), 4185–4199. doi:https://doi.org/10.1016/j.bmc.2019.07.049en
dc.identifier.urihttp://hdl.handle.net/10523/12237
dc.description.abstractChlamydia trachomatis high temperature requirement A (CtHtrA) is a serine protease that performs proteolytic and chaperone functions in pathogenic Chlamydiae; and is seen as a prospective drug target. This study details the strategies employed in optimizing the irreversible CtHtrA inhibitor JO146 [Boc-Val-Pro-ValP(OPh)2] for potency and selectivity. A series of adaptations both at the warhead and specificity residues P1 and P3 yielded 23 analogues, which were tested in human neutrophil elastase (HNE) and CtHtrA enzyme assays as well as Chlamydia cell culture assays. Trypsin and chymotrypsin inhibition assays were also conducted to measure off-target selectivity. Replacing the phosphonate moiety with α-ketobenzothiazole produced a reversible analogue with considerable CtHtrA inhibition and cell culture activity. Tertiary leucine at P3 (8a) yielded approximately 33-fold increase in CtHtrA inhibitory activity, with an IC50 = 0.68 ± 0.02 µM against HNE, while valine at P1 retained the best anti-chlamydial activity. This study provides a pathway for obtaining clinically relevant inhibitors.en_NZ
dc.format.mimetypeapplication/pdf
dc.language.isoenen_NZ
dc.publisherElsvieren_NZ
dc.relation.ispartofBioorg Med Chemen_NZ
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectChlamydia trachomatisen_NZ
dc.subjectHtrA inhibitoren_NZ
dc.titleStructure-Activity Analysis of Peptidic Chlamydia HtrA Inhibitorsen_NZ
dc.typeJournal Articleen_NZ
dc.date.updated2021-08-26T22:58:19Z
otago.schoolSchool of Pharmacyen_NZ
otago.relation.issue10en_NZ
otago.relation.volume27en_NZ
dc.identifier.doihttps://doi.org/10.1016/j.bmc.2019.07.049en_NZ
otago.bitstream.endpage4199en_NZ
otago.bitstream.startpage4185en_NZ
dc.rights.statementBioorg Med Chem, 27, 2019, 4185-4199, https://doi.org/10.1016/j.bmc.2019.07.049en_NZ
dc.description.refereedPeer Revieweden_NZ
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Attribution-NonCommercial-NoDerivatives 4.0 International
Except where otherwise noted, this item's licence is described as Attribution-NonCommercial-NoDerivatives 4.0 International