Structure-activity analysis of peptidic Chlamydia HtrA inhibitors

Ayodeji A Agbowuro; Jimin Hwang; Emma Peel; Rami Mazraani; Alexandra Springwald; James W Marsh; Laura McCaughey; Allan B Gamble; Wilhelmina M Huston; Joel D A Tyndall

doi:10.1016/j.bmc.2019.07.049

Structure-activity analysis of peptidic Chlamydia HtrA inhibitors

Bioorg Med Chem. 2019 Sep 15;27(18):4185-4199. doi: 10.1016/j.bmc.2019.07.049. Epub 2019 Jul 30.

Authors

Affiliations

¹ School of Pharmacy, University of Otago, Dunedin 9054, New Zealand.
² School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW 2006, Australia.
³ School of Life Sciences, University of Technology Sydney, 15 Broadway, Ultimo, NSW 2007, Australia.
⁴ The iThree Institute, University of Technology Sydney, 15 Broadway, Ultimo, NSW 2007, Australia.
⁵ The iThree Institute, University of Technology Sydney, 15 Broadway, Ultimo, NSW 2007, Australia; Department of Biochemistry, University of Oxford, South Park Road, Oxford OX1 3QU, United Kingdom.
⁶ School of Life Sciences, University of Technology Sydney, 15 Broadway, Ultimo, NSW 2007, Australia. Electronic address: Wilhelmina.Huston@uts.edu.au.
⁷ School of Pharmacy, University of Otago, Dunedin 9054, New Zealand. Electronic address: joel.tyndall@otago.ac.nz.

PMID: 31395511
DOI: 10.1016/j.bmc.2019.07.049

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-Val^P(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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Chlamydia trachomatis / pathogenicity*
Humans
Peptides / chemistry*
Structure-Activity Relationship

Substances

Peptides