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dc.contributor.authorAgbowuro, Ayodeji
dc.contributor.authorMazraani, Rami
dc.contributor.authorMcCaughey, Laura
dc.contributor.authorHuston, Wilhelmina
dc.contributor.authorGamble, Allan
dc.contributor.authorTyndall, Joel
dc.date.available2021-07-20T00:14:21Z
dc.date.copyright2018-10-12
dc.identifier.citationTetrahedron 74 (2018) 1184-1190en_NZ
dc.identifier.urihttp://hdl.handle.net/10523/12122
dc.description.abstractJO146, a mixture of two diastereomers of a peptidic phosphonate inhibitor for Chlamydial HtrA (CtHtrA), has reported activity against Chlamydia species in both human and koala. In this study we isolated the individual diastereomers JO146-D1 and JO146-D2 (in > 90% purity) and assessed their individual inhibitory activity against the serine protease human neutrophil elastase (HNE) which is structurally related to CtHtrA, as well as in Chlamydia trachomatis cell culture. JO146-D2 [S,S,R-Boc-Val-Pro-ValP(OPh)2], the isomer with the physiologically relevant valine at P1, had an approximate 2.5-fold in-crease in in vitro HNE inhibition potency over JO146-D1 [S,S,S-Boc-Val-Pro-ValP(OPh)2] and greater than 100-fold increase in cellular anti-chlamydial activity compared to JO146-D1 which possesses the unnatural valine at P1. JO146 and the individual diastereomers had excellent selectivity for the serine protease HNE over the potential off-target serine proteases trypsin and chymotrypsin. Docking studies supported the biological data with a geometrically unfavoured interaction observed between the P1 valine residue of JO146-D1 and the enzyme S1 sub-pocket.en_NZ
dc.format.mimetypeapplication/vnd.openxmlformats-officedocument.wordprocessingml.document
dc.language.isoenen_NZ
dc.publisherElsevieren_NZ
dc.relation.ispartofTetrahedronen_NZ
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.titleStereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146en_NZ
dc.typeJournal Articleen_NZ
dc.date.updated2021-07-19T23:42:21Z
otago.schoolSchool of Pharmacyen_NZ
otago.relation.volume74en_NZ
dc.identifier.doihttps://doi.org/10.1016/j.tet.2017.10.031en_NZ
otago.bitstream.endpage1190en_NZ
otago.bitstream.startpage1184en_NZ
dc.rights.statementhttps://doi.org/10.1016/j.tet.2017.10.031en_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