Molecular targets for Chagas disease: validation, challenges and lead compounds for widely exploited targets
Mariana Laureano de Souza, Thibault Joseph William Jacques Dit Lapierre, Gabriel Marques, Wítor Ribeiro Ferraz, André Berndt Penteado, Gustavo Henrique Goulart Trossini, Silvane Maria Fonseca Murta, Renata Barbosa de Oliveira, Celso de Oliveira Rezende Júnior, Rafaela Salgado Ferreira
Abstract
Introduction Chagas disease (CD) imposes social and economic burdens, yet the available treatments have limited efficacy in the disease’s chronic phase and cause serious adverse effects. To address this challenge, target-based approaches are a possible strategy to develop new, safe, and active treatments for both phases of the disease.Areas covered This review delves into target-based approaches applied to CD drug discovery, emphasizing the studies from the last five years. We highlight the proteins cruzain (CZ), trypanothione reductase (TR), sterol 14 α-demethylase (CPY51), iron superoxide dismutase (Fe-SOD), proteasome, cytochrome b (Cytb), and cleavage and polyadenylation specificity factor 3 (CPSF3), chosen based on their biological and chemical validation as drug targets. For each, we discuss its biological relevance and validation as a target, currently related challenges, and the status of the most promising inhibitors.Expert opinion Target-based approaches toward developing potential CD therapeutics have yielded promising leads in recent years. We expect a significant advance in this field in the next decade, fueled by the new options for Trypanosoma cruzi genetic manipulation that arose in the past decade, combined with recent advances in computational chemistry and chemical biology.