Comparative high-throughput analysis of the <i>Trypanosoma cruzi</i> response to organometallic compounds

Mosquillo, M. Florencia; Smircich, Pablo; Ciganda, Martı́n; Lima, Analı́a; Gambino, Dinorah; Garat, Beatríz; Pérez-Díaz, Leticia

doi:10.1039/d0mt00030b

Cited by 13 publications

(24 citation statements)

References 81 publications

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“…Fexinidazole, an NTR-1-activated 5-nitroimidazole pro-drug [ 31 ], has been shown to outperform both benznidazole and nifurtimox as a curative treatment for experimental T. cruzi infections [ 34 ] ( Figure 2 A,B, as example), and a clinical trial to assess efficacy and tolerability against patients with asymptomatic chronic infections has been undertaken [ 35 ]. In addition, there have also been a number of recent studies reporting encouraging preliminary data on the antiparasite activities of other novel nitroaromatics [ 88 ], and of a new generation of diverse organometallic compounds [ 89 , 90 , 91 , 92 ].…”

Section: Progress In Chagas Disease Drug Developmentmentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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The protozoan parasite Trypanosoma cruzi causes Chagas disease, an important public health problem throughout Latin America. Current therapeutic options are characterised by limited efficacy, long treatment regimens and frequent toxic side-effects. Advances in this area have been compromised by gaps in our knowledge of disease pathogenesis, parasite biology and drug activity. Nevertheless, several factors have come together to create a more optimistic scenario. Drug-based research has become more systematic, with increased collaborations between the academic and commercial sectors, often within the framework of not-for-profit consortia. High-throughput screening of compound libraries is being widely applied, and new technical advances are helping to streamline the drug development pipeline. In addition, drug repurposing and optimisation of current treatment regimens, informed by laboratory research, are providing a basis for new clinical trials. Here, we will provide an overview of the current status of Chagas disease drug development, highlight those areas where progress can be expected, and describe how fundamental research is helping to underpin the process.

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Section: Progress In Chagas Disease Drug Developmentmentioning

confidence: 99%

Challenges in Chagas Disease Drug Development

et al. 2020

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“…Their effect on some selected molecular targets was studied and omic studies were performed for the most promising pyridine-2-thiolato-1oxide (mpo) compounds. In general, the inclusion of the ferrocene moiety led to interesting effects on the biological profile of the compounds (Rodríguez Arce et al, 2015;Mosquillo et al, 2018a;Mosquillo et al, 2018b;Rivas et al, 2018;Rivas et al, 2019;Rodríguez Arce et al, 2019;Mosquillo et al, 2020;Rivas et al, 2021).…”

Section: Ferrocenyl Derivativesmentioning

confidence: 99%

“…High-throughput omic studies have proved to be powerful tools for going further into the basic biology of parasites like T. cruzi and also for the validation of drug targets (Atwood et al, 2005;Chávez et al, 2017;García-Huertas et al, 2017;Van den Kerkhof et al, 2020). Although these studies have been also used to explore organic drugs action in kinetoplastid parasites, similar studies for metal-based drugs were not reported until part of our group recently performed a high throughput omic study on T. cruzi for the two analogous Pt and Pd organometallic hit compounds [M II (dppf)(mpo)](PF 6 ) (Mosquillo et al, 2018a;Mosquillo et al, 2018b;Mosquillo et al, 2020).…”

Section: Ferrocenyl Derivativesmentioning

confidence: 99%

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Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

Gambino

Otero

2022

Front. Chem.

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Human African Trypanosomiasis (HAT), Chagas disease or American Trypanosomiasis (CD), and leishmaniases are protozoan infections produced by trypanosomatid parasites belonging to the kinetoplastid order and they constitute an urgent global health problem. In fact, there is an urgent need of more efficient and less toxic chemotherapy for these diseases. Medicinal inorganic chemistry currently offers an attractive option for the rational design of new drugs and, in particular, antiparasitic ones. In this sense, one of the main strategies for the design of metal-based antiparasitic compounds has been the coordination of an organic ligand with known or potential biological activity, to a metal centre or an organometallic core. Classical metal coordination complexes or organometallic compounds could be designed as multifunctional agents joining, in a single molecule, different chemical species that could affect different parasitic targets. This review is focused on the rational design of palladium(II) and platinum(II) compounds with bioactive ligands as prospective drugs against trypanosomatid parasites that has been conducted by our group during the last 20 years.

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“…Among the affected pathways, the biosynthesis of ergosterol was found to be modulated by the compounds. [12][13] Ergosterol is essential for providing structure and function of membranes and the parasite is entirely dependent on these endogenously produced sterols for survival and proliferation. Since the enzymes involved in this metabolic pathway are different to their counterparts in the mammalian host, the set of enzymes that participate in the pathway are recognized as attractive targets for antichagasic drugs discovery.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2023

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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.

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Comparative high-throughput analysis of the Trypanosoma cruzi response to organometallic compounds

Abstract: An in-depth, comparative look at the effects of two structurally related organometallic Pd and Pt compounds on the global gene expression pattern of T. cruzi epimastigotes. This parasite is the causative agent of Chagas disease.

Cited by 13 publications

References 81 publications

Challenges in Chagas Disease Drug Development

Challenges in Chagas Disease Drug Development

Facing Diseases Caused by Trypanosomatid Parasites: Rational Design of Pd and Pt Complexes With Bioactive Ligands

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

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