Drug discovery for Chagas disease should consider Trypanosoma cruzi strain diversity

Abstract

This opinion piece presents an approach to standardisation of an important aspect of Chagas disease drug discovery and development: selecting Trypanosoma cruzi strains for in vitro screening. We discuss the rationale for strain selection representing T. cruzi diversity and provide recommendations on the preferred parasite stage for drug discovery, T. cruzi discrete typing units to include in the panel of strains and the number of strains/clones for primary screens and lead compounds. We also consider experimental approaches for in vitro drug assays. The Figure illustrates the current Chagas disease drug-discovery and development landscape.

Chagas disease drug discovery and development landscape in 2013/2014. Research activities: public and private partners are engaged in the screening of chemical libraries, hit to lead and lead optimisation of new series for Chagas disease treatment; Translational activities: pre-clinical studies, Phase I and IIa studies with new compounds are underway; Development activities: two double-blind, placebo-controlled clinical trials are testing the potential beneficial effects of benznidazole (BZ) in chronic Chagas disease. The Argentine company Elea Laboratories is manufacturing the generic version of BZ under the tradename Abarax. Paediatric formulations of BZ and nifurtimox are being implemented. BENEFIT: Benznidazole Evaluation for Interrupting Trypanosomiasis; BERENICE: Benznidazole and Triazole Research Group for Nanomedicine and Innovation on Chagas Disease; Broad: Broad Institute; DDU@Dundee: Drug Discovery Unit at Dundee University; DNDi: Drugs for Neglected Diseases initiative; GNF: Genomics Institute of the Novartis Research Foundation; IPK: Institute Pasteur Korea; LSTMH: London School of Tropical Medicine & Hygiene; NYU: New York University; STPH: Swiss Tropical and Public Health Institute; TRAENA: Tratamiento con Benznidazol en pacientes Adultos con Enfermedad de Chagas Crónica; UGA: University of Georgia.