Structure-activity analysis of peptidic Chlamydia HtrA inhibitors

Agbowuro, AA; Hwang, J; Peel, E; Mazraani, R; Springwald, A; Marsh, JW; McCaughey, L; Gamble, AB; Huston, WM; Tyndall, JDA

Structure-activity analysis of peptidic Chlamydia HtrA inhibitors

Agbowuro, AA Hwang, J Peel, E Mazraani, R Springwald, A Marsh, JW

McCaughey, L

Gamble, AB Huston, WM

Tyndall, JDA

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Publication Type:: Journal Article
Citation:: Bioorganic and Medicinal Chemistry, 2019, 27 (18), pp. 4185 - 4199
Issue Date:: 2019-09-15

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Field	Value	Language
dc.contributor.author	Agbowuro, AA	en_US
dc.contributor.author	Hwang, J	en_US
dc.contributor.author	Peel, E	en_US
dc.contributor.author	Mazraani, R	en_US
dc.contributor.author	Springwald, A	en_US
dc.contributor.author	Marsh, JW https://orcid.org/0000-0003-4681-1012	en_US
dc.contributor.author	McCaughey, L https://orcid.org/0000-0001-5897-0163	en_US
dc.contributor.author	Gamble, AB	en_US
dc.contributor.author	Huston, WM https://orcid.org/0000-0002-0879-1287	en_US
dc.contributor.author	Tyndall, JDA	en_US
dc.date.available	2019-07-29	en_US
dc.date.issued	2019-09-15	en_US
dc.identifier.citation	Bioorganic and Medicinal Chemistry, 2019, 27 (18), pp. 4185 - 4199	en_US
dc.identifier.issn	0968-0896	en_US
dc.identifier.uri	http://hdl.handle.net/10453/135496
dc.description.abstract	© 2019 Elsevier Ltd Chlamydia 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_US
dc.relation.ispartof	Bioorganic and Medicinal Chemistry	en_US
dc.relation.isbasedon	10.1016/j.bmc.2019.07.049	en_US
dc.rights	info:eu-repo/semantics/embargoedAccess
dc.subject.classification	Medicinal & Biomolecular Chemistry	en_US
dc.title	Structure-activity analysis of peptidic Chlamydia HtrA inhibitors	en_US
dc.type	Journal Article
utslib.citation.volume	18	en_US
utslib.citation.volume	27	en_US
utslib.for	0304 Medicinal and Biomolecular Chemistry	en_US
utslib.for	0305 Organic Chemistry	en_US
utslib.for	1115 Pharmacology and Pharmaceutical Sciences	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	open_access	*
utslib.copyright.embargo	2021-09-16T00:00:00+1000
pubs.issue	18	en_US
pubs.publication-status	Published	en_US
pubs.volume	27	en_US

Abstract:

© 2019 Elsevier Ltd Chlamydia 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.

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http://hdl.handle.net/10453/135496