Prodrugs as new therapies against Chagas disease: In vivo synergy between Trypanosoma cruzi proline racemase inhibitors and benznidazole - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Journal of Global Antimicrobial Resistance Année : 2022

Prodrugs as new therapies against Chagas disease: In vivo synergy between Trypanosoma cruzi proline racemase inhibitors and benznidazole

Résumé

Objective: Chagas disease, caused by the parasitic protozoan Trypanosoma cruzi, affects approximately 6-7 million people worldwide. There are limited available therapies, and they exhibit low efficacy, often high toxicity in chronic cases and some drug resistance. In this study, our objective was to develop ester prodrugs that inhibit proline racemase (TcPRAC), a parasitic enzyme that we have previously identified and characterized as a promising target because of its essential role in the parasite's life cycle and virulence, and to test their activity against T. cruzi. Method: Using structural bioinformatics, we modelled several functional intermediates of the catalytic site between the opened and closed conformations of TcPRAC based on its crystal structures in complex with its competitive inhibitor, pyrrole-2-carboxylic acid. Guided by these intermediates, which were later validated in cocrystals, we designed and evaluated numerous compounds and tested them enzymatically on live parasites and in mice with our quick and straightforward drug screening method, which is based on state-of-the-art bioluminescent T. cruzi parasites injected subcutaneously. Results: Some of our novel compounds specifically inhibited racemase activity, as determined through biochemical assays, and covalently bound to TcPRAC. Furthermore, the corresponding ester prodrugs were effective in killing parasites in vitro. Bioluminescent T. cruzi assays in mice showed that JR1531, a TcPRAC inhibitor prodrug, can kill parasites in living animals, with boosted action when combined with low doses of benznidazole. Conclusions: This approach, based on TcPRAC inhibitor prodrugs in association with low doses of benznidazole, may lead to a more effective, specific and nontoxic therapy against Chagas disease.
Fichier principal
Vignette du fichier
Dias de Melo_1-s2.0-S2213716521002794-main.pdf (1.48 Mo) Télécharger le fichier
Dias de Melo_1-s2.0-S2213716521002794-mmc1.zip (785.67 Ko) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03504248 , version 1 (30-05-2022)

Licence

Paternité

Identifiants

Citer

Guilherme Dias de Melo, Nicolas Coatnoan, Nicolas Gouault, Jean-François Cupif, Jacques Renault, et al.. Prodrugs as new therapies against Chagas disease: In vivo synergy between Trypanosoma cruzi proline racemase inhibitors and benznidazole. Journal of Global Antimicrobial Resistance, 2022, 28, pp.84-89. ⟨10.1016/j.jgar.2021.10.030⟩. ⟨hal-03504248⟩
47 Consultations
29 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More