Phenotypic screening approaches for Chagas disease drug discovery

Chatelain, Eric; Ioset, Jean‐Robert

doi:10.1080/17460441.2018.1417380

Cited by 79 publications

(92 citation statements)

References 81 publications

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“…Drug repurposing or even combinations with the current drugs could be options to minimize this problem [59,120]. In this direction, phenotypic strategy has been considered the most valuable approach for the screening of antiparasitic compounds [172].…”

Section: Discussionmentioning

confidence: 99%

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Vannier‐Santos¹,

Brunoro²,

Soeiro³

et al. 2019

Biology OfTrypanosoma Cruzi

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Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic to Latin America, standing out as a socioeconomic problem for low-income tropical populations. Such disease affects millions of people worldwide and emerges in nonendemic areas due to migration and climate changes. The current chemotherapy is restricted to two nitroderivatives (benznidazole and nifurtimox), which is unsatisfactory due to limited efficacy (particularly in chronic phase) and adverse side effects. T. cruzi life cycle is complex, including invertebrate and vertebrate hosts and three developmental forms (epimastigotes, trypomastigotes, and amastigotes). In this chapter, we will discuss promising cellular and molecular targets present in the vertebrate-dwelling forms of the parasite (trypomastigotes and amastigotes). Among the cellular targets, the mitochondrion is the most frequently studied; while among the molecular ones, we highlight squalene synthase, C14α-sterol demethylase, and cysteine proteases. In this scenario, proteomics becomes a valuable tool for the identification of other molecular targets, and some previously identified candidates will be also discussed. Multidisciplinary studies are needed to identify novel key molecules in T. cruzi in order to increase trypanocidal activity and reduce mammalian toxicity, ensuring the development of novel drugs for Chagas disease.

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Section: Discussionmentioning

confidence: 99%

Parasite, Compartments, and Molecules: Trick versus Treatment on Chagas Disease

Vannier‐Santos¹,

Brunoro²,

Soeiro³

et al. 2019

Biology OfTrypanosoma Cruzi

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“…In general, three known major approaches to novel drug development, including antitrypanosomals, may be outlined: (i) ligand-based approach, (ii) target-based drug discovery [40], and (iii) phenotype-based drug discovery [41]. Different types of compounds, namely, thiosemicarbazones, thiazolidines, triazole-and furan-based compounds, benzofuran derivatives, peptidyl compounds, peptidomimetics acyland arylhydrazones, etc.…”

Section: Drug Discovery Strategiesmentioning

confidence: 99%

Thiazolidinone-Related Heterocyclic Compounds as Potential Antitrypanosomal Agents

Kryshchyshyn¹,

Kaminskyy²,

Grellier³

et al. 2021

Azoles - Synthesis, Properties, Applications and Perspectives

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Human African trypanosomiasis (HAT) and Chagas disease are neglected tropical diseases (NTDs) due to parasite protists from the Trypanosoma genus transmitted by insect vectors. Trypanosomiases affect mostly poor populations in the developing countries, and the development of new antitrypanosomal drugs is underinvested by governments and the pharmaceutical industry. In this chapter, we described the development of 4-thiazolidinone and thiazole derivatives with heterocyclic fragments which exhibit good inhibition of trypanosome growth and might constitute potential candidates for the development of new drugs against trypanosomiasis. Antitrypanosomal design, mainly within structure-based design, led to the synthesis of 5-ene-4-thiazolidinone-3-alkanecarboxylic acids; 2,3-disubstituted 4-thiazolidinones; thiazolidinone-pyrazoline, phenylindole-thiazolidinone, and imidazothiadiazole-thiazolidinone hybrids; as well as 4-thiazolidinone-based fused heterocycles, especially thiopyrano[2,3-d]thiazoles, and non-thiazolidinone compounds-namely, isothiocoumarine derivatives. Moreover, antitrypanosomal 4-thiazolidinones are of special interest in the search for new antimalarial and antileishmanial agents. Also many active anticancer agents among the abovementioned 4-thiazolidinones have been discovered.

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“…Trends in Parasitology cheminformatics, target-based MoA rationalization, or even multitarget drug profiling. Specifically, in parasitology, it is the clinical need in the field that is driving the shift toward screening campaign paradigms using phenotypic approaches [86]. For Chagas' disease, T. cruzi drug-discovery campaigns have, for several years, employed computational approaches using data from several public whole-cell, phenotypic high-throughput screens made available by the Broad Institute (including a single screen of over 300 000 molecules) [87].…”

Section: Outstanding Questionsmentioning

confidence: 99%