Structure-activity analysis of peptidic Chlamydia HtrA inhibitors

Agbowuro, A. A., Hwang, J., Peel, E., Mazraani, R., Springwald, A., Marsh, J. W., McCaughey, L. , Gamble, A. B., Huston, W. M. and Tyndall, J. D.A. (2019) Structure-activity analysis of peptidic Chlamydia HtrA inhibitors. Bioorganic and Medicinal Chemistry, 27(18), pp. 4185-4199. (doi: 10.1016/j.bmc.2019.07.049) (PMID:31395511)

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Abstract

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.

Item Type:Articles
Additional Information:This research was supported by grants from the Otago Medical Research Foundation (Grant no. AG 319), New Zealand Pharmacy Education and Research Foundation (Grant no. 250) and the University of Otago.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:MCCAUGHEY, Dr LAURA
Authors: Agbowuro, A. A., Hwang, J., Peel, E., Mazraani, R., Springwald, A., Marsh, J. W., McCaughey, L., Gamble, A. B., Huston, W. M., and Tyndall, J. D.A.
College/School:College of Medical Veterinary and Life Sciences > School of Life Sciences
Journal Name:Bioorganic and Medicinal Chemistry
Publisher:Elsevier
ISSN:0968-0896
ISSN (Online):1464-3391
Published Online:30 July 2019

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