Rate-of-Kill (RoK) assays to triage large compound sets for Chagas disease drug discovery: Application to GSK Chagas Box

by Juan Cantizani, Pablo Gamallo, Ignacio Cotillo, Raquel Alvarez-Velilla, Julio Martin Chagas disease (CD) is a human disease caused byTrypanosoma cruzi. Whilst endemic in Latin America, the disease is spread around the world due to migration flows, being estimated that 8 million people are infected worldwide and over 10,000 people die yearly of complications linked to CD. Current chemotherapeutics is restricted to only two drugs, i.e. benznidazole (BNZ) and nifurtimox (NIF), both being nitroaromatic compounds sharing mechanism of action and exerting suboptimal efficacy and serious adverse effects. Recent clinical trials conducted to reposition antifungal azoles have turned out disappointing due to poor efficacy outcomes despite their promising preclinical profile. This apparent lack of translation from bench models to the clinic raises the question of whether we are using the rightin vitro tools for compound selection. We propose that speed of action and cidality, rather than potency, are properties that can differentiate those compounds with better prospect of success to show efficacy in animal models of CD. Here we investigate the use ofin vitro assays looking at the kinetics of parasite kill as a valuable surrogate to tell apart slow- (i.e. azoles targeting CYP51) and fast-acting (i.e. nitroaromatic) compounds. Data analysis and experimental design have been optimised to make it amenable for high-throughput compound profiling. Automated data reduction of experimental ki...
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research