State-of-the-Art in the Drug Discovery Pathway for Chagas Disease: A Framework for Drug Development and Target Validation

Abstract

Chagas disease is the most important protozoan infection in the Americas, and constitutes a significant public health concern throughout the world. Development of new medications against its etiologic agent, Trypanosoma cruzi, has been traditionally slow and difficult, lagging in comparison with diseases caused by other kinetoplastid parasites. Among the factors that explain this are the incompletely understood mechanisms of pathogenesis of T. cruzi infection and its complex set of interactions with the host in the chronic stage of the disease. These demand the performance of a variety of in vitro and in vivo assays as part of any drug development effort. In this review, we discuss recent breakthroughs in the understanding of the parasite’s life cycle and their implications in the search for new chemotherapeutics. For this, we present a framework to guide drug discovery efforts against Chagas disease, considering state-of-the-art preclinical models and recently developed tools for the identification and validation of molecular targets.

Keywords:

• Chagas disease
• Trypanosoma cruzi
• drug development
• screenings
• target
• animal models

Acknowledgments

We appreciate the support of the Generalitat of Catalonia Universities and Research Department, Spain (AGAUR: 2021 SGR 01562). The work of N.M.-P., J.C.G.-F., and J.G. was supported by the ISCIII project PI18/01054. This research was supported by CIBER - Consorcio Centro de. Investigación Biomédica en Red - (CB 2021), Instituto de Salud Carlos III, Ministerio de Ciencia e. Innovación and Unión Europea – NextGenerationEU. We also acknowledge the support from the Spanish Ministry of Science, Innovation, and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023′′ Program (CEX2018-000806-S funded by MCIN/AEI/ 10.13039/501100011033) and from the Generalitat of Catalonia through the “CERCA Program.” J.C.G.-F. received support through a fellowship from “la Caixa” Foundation (ID 100010434, fellowship code: LCF/BQ/DI21/11860037). The Drugs for Neglected Diseases initiative (DNDi) is grateful to its donors, public and private, who have provided funding to DNDi since its inception in 2003. A full list of DNDi’s donors can be found at http://www.dndi.org/donors/donors/.

Disclosure

The authors report no conflicts of interest in this work.