Platinum and Palladium Organometallic Compounds: Disrupting the Ergosterol Pathway in Trypanosoma cruzi.
CYP51 enzyme
PMK enzyme
Trypanosoma cruzi
ergosterol biosynthesis
metal-based drugs
Journal
Chembiochem : a European journal of chemical biology
ISSN: 1439-7633
Titre abrégé: Chembiochem
Pays: Germany
ID NLM: 100937360
Informations de publication
Date de publication:
04 Oct 2023
04 Oct 2023
Historique:
revised:
22
06
2023
received:
30
05
2023
pubmed:
29
6
2023
medline:
29
6
2023
entrez:
29
6
2023
Statut:
ppublish
Résumé
Current treatment for Chagas' disease is based on two drugs, Nifurtimox and Benznidazol, which have limitations that reduce the effectiveness and continuity of treatment. Thus, there is an urgent need to develop new, safe and effective drugs. In previous work, two new metal-based compounds with trypanocidal activity, Pd-dppf-mpo and Pt-dppf-mpo, were fully characterized. To unravel the mechanism of action of these two analogous metal-based drugs, high-throughput omics studies were performed. A multimodal mechanism of action was postulated with several candidates as molecular targets. In this work, we validated the ergosterol biosynthesis pathway as a target for these compounds through the determination of sterol levels by HPLC in treated parasites. To understand the molecular level at which these compounds participate, two enzymes that met eligibility criteria at different levels were selected for further studies: phosphomevalonate kinase (PMK) and lanosterol 14-α demethylase (CYP51). Molecular docking processes were carried out to search for potential sites of interaction for both enzymes. To validate these candidates, a gain-of-function strategy was used through the generation of overexpressing PMK and CYP51 parasites. Results here presented confirm that the mechanism of action of Pd-dppf-mpo and Pt-dppf-mpo compounds involves the inhibition of both enzymes.
Identifiants
pubmed: 37382991
doi: 10.1002/cbic.202300406
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202300406Subventions
Organisme : Programa de Desarrollo de las Ciencias Básicas (PEDECIBA)
Organisme : Comisión académica de Posgrados
ID : AP_2019_63
Organisme : Comisión académica de Posgrados
ID : CAP_2022_36
Informations de copyright
© 2023 Wiley-VCH GmbH.
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