Platinum and Palladium Organometallic Compounds: Disrupting the Ergosterol Pathway in Trypanosoma cruzi

Abstract

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.

Metallomics: An Essential Tool for the Study of Potential Antiparasitic Metallodrugs

“…Moreover, two enzymes of the pathway, namely, phosphomevalonate kinase (PMK) and lanosterol 14α-demethylase (CYP51), were selected as targets for a further study by molecular docking, which showed an energetically favorable interaction with the compounds. These observations were experimentally verified after the study of PMK and CYP51 overexpressing parasites, confirming that the hit compounds were involved in the inhibition of both enzymes, leading to a decrease in ergosterol levels in the parasites …”

“…This multiomics approach allowed us to unravel significant differences between the analogous hit compounds, highlighting once again the importance of the nature of the metallic core on the biological behavior of metallodrugs . Since ergosterol biosynthesis turned out to be modulated by the two hit compounds, a subsequent study comprising the determination of sterol levels in treated parasites was performed, which confirmed the involvement of [Pd II (dppf)­(mpo)]­(PF 6 ) and [Pt II (dppf)­(mpo)]­(PF 6 ) in this biosynthetic pathway . Moreover, two enzymes of the pathway, namely, phosphomevalonate kinase (PMK) and lanosterol 14α-demethylase (CYP51), were selected as targets for a further study by molecular docking, which showed an energetically favorable interaction with the compounds.…”

“…In this regard, we have focused our attention on the rational design of antiparasitic metal compounds based on the relationships between chemical structure, physicochemical properties, and biological activity obtained in our investigations. This research line has led to important contributions that have been transferred to the scientific field, showing the vital importance of cellular uptake metallomic studies to understand the fate of potential metallodrugs and elucidate targets and mechanisms of action. − Table summarizes the uptake results obtained after metallomics studies of different metal-based compounds performed on epimastigotes of Trypanosoma cruzi. The molecular structures of the bioactive compounds are shown in Figure .…”

“…In this context, Gambino’s group has been working during the last 20–25 years on the rational design of novel metal-based compounds bearing activity against these trypanosomatid parasites, with a particular focus on the causative agent of Chagas disease, Trypanosoma cruzi. − , Although metallomics and omics studies in general have been performed in the development of anticancer metal-based drugs, an omics strategy had not been explored for unraveling the mechanism of action of antiparasitic metal-based prospective drugs. Knowing the significance of omics studies in drug development, metallomics, proteomics, and transcriptomics of several metal-based compounds were performed for the first time in Trypanosoma cruzi by us. − The current review involves the comparative study of the new knowledge obtained by our group through this approach.…”

“… 40 Since ergosterol biosynthesis turned out to be modulated by the two hit compounds, a subsequent study comprising the determination of sterol levels in treated parasites was performed, which confirmed the involvement of [Pd II (dppf)(mpo)](PF 6 ) and [Pt II (dppf)(mpo)](PF 6 ) in this biosynthetic pathway. 41 Moreover, two enzymes of the pathway, namely, phosphomevalonate kinase (PMK) and lanosterol 14α-demethylase (CYP51), were selected as targets for a further study by molecular docking, which showed an energetically favorable interaction with the compounds. These observations were experimentally verified after the study of PMK and CYP51 overexpressing parasites, confirming that the hit compounds were involved in the inhibition of both enzymes, leading to a decrease in ergosterol levels in the parasites.…”