Optimization of peptide-based inhibitors targeting the HtrA serine protease in Chlamydia: Design, synthesis and biological evaluation of pyridone-based and N-Capping group-modified analogues.

Autor: Hwang J; School of Pharmacy, University of Otago, Dunedin, 9054, New Zealand., Strange N; School of Life Sciences, Faculty of Science, University of Technology Sydney, New South Wales, Australia., Phillips MJA; School of Life Sciences, Faculty of Science, University of Technology Sydney, New South Wales, Australia., Krause AL; Department of Microbiology and Immunology, University of Otago, Dunedin, 9054, New Zealand., Heywood A; Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, 9054, New Zealand., Gamble AB; School of Pharmacy, University of Otago, Dunedin, 9054, New Zealand. Electronic address: allan.gamble@otago.ac.nz., Huston WM; School of Life Sciences, Faculty of Science, University of Technology Sydney, New South Wales, Australia. Electronic address: Wilhelmina.Huston@uts.edu.au., Tyndall JDA; School of Pharmacy, University of Otago, Dunedin, 9054, New Zealand. Electronic address: joel.tyndall@otago.ac.nz.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2021 Nov 15; Vol. 224, pp. 113692. Date of Electronic Publication: 2021 Jul 07.
DOI: 10.1016/j.ejmech.2021.113692
Abstrakt: The obligate intracellular bacterium Chlamydia trachomatis (C. trachomatis) is responsible for the most common bacterial sexually transmitted infection and is the leading cause of preventable blindness, representing a major global health burden. While C. trachomatis infection is currently treatable with broad-spectrum antibiotics, there would be many benefits of a chlamydia-specific therapy. Previously, we have identified a small-molecule lead compound JO146 [Boc-Val-Pro-Val P (OPh) 2 ] targeting the bacterial serine protease HtrA, which is essential in bacterial replication, virulence and survival, particularly under stress conditions. JO146 is highly efficacious in attenuating infectivity of both human (C. trachomatis) as well as koala (C. pecorum) species in vitro and in vivo, without host cell toxicity. Herein, we present our continuing efforts on optimizing JO146 by modifying the N-capping group as well as replacing the parent peptide structure with the 2-pyridone scaffold at P3/P2. The drug optimization process was guided by molecular modelling, enzyme and cell-based assays. Compound 18b from the pyridone series showed improved inhibitory activity against CtHtrA by 5-fold and selectivity over human neutrophil elastase (HNE) by 109-fold compared to JO146, indicating that 2-pyridone is a suitable bioisostere of the P3/P2 amide/proline for developing CtHtrA inhibitors. Most pyridone-based inhibitors showed superior anti-chlamydial potency to JO146 especially at lower doses (25 and 50 μM) in C. trachomatis and C. pecorum cell culture assays. Modifications of the N-capping group of the peptidyl inhibitors did not have much influence on the anti-chlamydial activities, providing opportunities for more versatile alterations and future optimization. In summary, we present 2-pyridone based analogues as a new generation of non-peptidic CtHtrA inhibitors, which hold better promise as anti-chlamydial drug candidates.
Competing Interests: Declaration of competing interest The authors have no conflicts of interest.
(Copyright © 2021 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: