Structure-activity analysis of peptidic Chlamydia HtrA inhibitors
| Autor: | Rami Mazraani, Alexandra Springwald, Emma Peel, Allan B. Gamble, Jimin Hwang, Joel D. A. Tyndall, James W. Marsh, Wilhelmina M. Huston, Laura C. McCaughey, Ayodeji A. Agbowuro |
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| Rok vydání: | 2019 |
| Předmět: |
Medicinal & Biomolecular Chemistry
Clinical Biochemistry Pharmaceutical Science Chlamydia trachomatis medicine.disease_cause 01 natural sciences Biochemistry Structure-Activity Relationship Drug Discovery medicine Humans Molecular Biology Serine protease Chymotrypsin biology 010405 organic chemistry Chemistry Organic Chemistry Elastase Trypsin 0104 chemical sciences 010404 medicinal & biomolecular chemistry Cell culture biology.protein Molecular Medicine Leucine Peptides Cell culture assays medicine.drug |
| Zdroj: | Bioorganic & Medicinal Chemistry. 27:4185-4199 |
| ISSN: | 0968-0896 |
| Popis: | © 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. |
| Databáze: | OpenAIRE |
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