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

Agbowuro, A. A., Mazraani, R., McCaughey, L. C. , Huston, W. M., Gamble, A. B. and Tyndall, J. D.A. (2018) Stereochemical basis for the anti-chlamydial activity of the phosphonate protease inhibitor JO146. Tetrahedron, 74(12), pp. 1184-1190. (doi: 10.1016/j.tet.2017.10.031)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: MCCAUGHEY, Dr LAURA
• Authors: Agbowuro, A. A., Mazraani, R., McCaughey, L. C., Huston, W. M., Gamble, A. B., and Tyndall, J. D.A.
• College/School: College of Medical Veterinary and Life Sciences
• Journal Name: Tetrahedron
• Publisher: Elsevier
• ISSN: 0040-4020
• ISSN (Online): 1464-5416
• Published Online: 12 October 2017
• Copyright Holders: Copyright © 2017 Elsevier Ltd.
• First Published: First published in Tetrahedron 74(12):1184-1190
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher