Identification of Trypanocidal Activity for Known Clinical Compounds Using a New Trypanosoma cruzi Hit-Discovery Screening Cascade.

• Published in: PLOS Neglected Tropical Diseases
• Main Authors: Manu De Rycker, John Thomas, Jennifer Riley, Stephen J Brough, Tim J Miles, David W Gray
• Format: Article in Journal/Newspaper
• Language: English
• Published: Public Library of Science (PLoS) 2016
• Subjects: Arctic medicine. Tropical medicine; RC955-962; Public aspects of medicine; RA1-1270; Arctic
• Online Access: https://doi.org/10.1371/journal.pntd.0004584; https://doaj.org/article/71682c789615451a96ec345def4d4288

Chagas disease is a significant health problem in Latin America and the available treatments have significant issues in terms of toxicity and efficacy. There is thus an urgent need to develop new treatments either via a repurposing strategy or through the development of new chemical entities. A key first step is the identification of compounds with anti-Trypanosoma cruzi activity from compound libraries. Here we describe a hit discovery screening cascade designed to specifically identify hits that have the appropriate anti-parasitic properties to warrant further development. The cascade consists of a primary imaging-based assay followed by newly developed and appropriately scaled secondary assays to predict the cidality and rate-of-kill of the compounds. Finally, we incorporated a cytochrome P450 CYP51 biochemical assay to remove compounds that owe their phenotypic response to inhibition of this enzyme. We report the use of the cascade in profiling two small libraries containing clinically tested compounds and identify Clemastine, Azelastine, Ifenprodil, Ziprasidone and Clofibrate as molecules having appropriate profiles. Analysis of clinical derived pharmacokinetic and toxicity data indicates that none of these are appropriate for repurposing but they may represent suitable start points for further optimisation for the treatment of Chagas disease.