Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146

Agbowuro, AA; Mazraani, R; McCaughey, LC; Huston, WM; Gamble, AB; Tyndall, JDA

Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146

Agbowuro, AA Mazraani, R McCaughey, LC

Huston, WM

Gamble, AB Tyndall, JDA

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Publication Type:: Journal Article
Citation:: Tetrahedron, 2018, 74 (12), pp. 1184 - 1190
Issue Date:: 2018-03-22

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Field	Value	Language
dc.contributor.author	Agbowuro, AA	en_US
dc.contributor.author	Mazraani, R	en_US
dc.contributor.author	McCaughey, LC https://orcid.org/0000-0001-5897-0163	en_US
dc.contributor.author	Huston, WM https://orcid.org/0000-0002-0879-1287	en_US
dc.contributor.author	Gamble, AB	en_US
dc.contributor.author	Tyndall, JDA	en_US
dc.date.issued	2018-03-22	en_US
dc.identifier.citation	Tetrahedron, 2018, 74 (12), pp. 1184 - 1190	en_US
dc.identifier.issn	0040-4020	en_US
dc.identifier.uri	http://hdl.handle.net/10453/122005
dc.description.abstract	© 2017 Elsevier Ltd JO146, 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 and functionally 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 increase 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_US
dc.relation.ispartof	Tetrahedron	en_US
dc.relation.isbasedon	10.1016/j.tet.2017.10.031	en_US
dc.subject.classification	Organic Chemistry	en_US
dc.title	Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146	en_US
dc.type	Journal Article
utslib.citation.volume	12	en_US
utslib.citation.volume	74	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
pubs.embargo.period	Not known	en_US
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - ithree - Institute of Infection, Immunity and Innovation
utslib.copyright.status	closed_access
pubs.issue	12	en_US
pubs.publication-status	Published	en_US
pubs.volume	74	en_US

Abstract:

© 2017 Elsevier Ltd JO146, 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 and functionally 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 increase 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.

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http://hdl.handle.net/10453/122005