Modelling data for: Short-course combination treatment for experimental chronic Chagas disease

<p><span>Chagas disease, caused by the protozoan parasite <em>Trypanosoma</em> <em>cruzi</em>, affects millions of people in the Americas and across the world leading to considerable morbidity and mortality. Current treatment options, benznidazole (BNZ) and nifurtimox, offer limited efficacy and often lead to adverse side effects due to long treatment durations. Better treatment options are therefore urgently required. Here we describe a pyrrolopyrimidine series, identified through phenotypic screening, that offers a clear opportunity to improve on current treatments. In vitro cell-based washout assays demonstrate that compounds in the series are incapable of killing all parasites, however, combining these pyrrolopyrimidines with a sub-efficacious dose of BNZ can clear all parasites in vitro after five days. Importantly, these findings were replicated in a clinically predictive<em> in vivo</em> model of chronic Chagas disease, where five days of treatment with the combination was sufficient to prevent parasite relapse. Comprehensive mechanism of action studies, supported by ligand-structure modelling, show that compounds from this pyrrolopyrimidine series inhibit the Q</span>_{<span>i</span>}<span> active site of <em>T. cruzi</em> cytochrome <em>b</em>, part of the cytochrome <em>bc1</em> complex of the electron transport chain. Knowledge of the molecular target enabled a cascade of assays to be assembled to evaluate selectivity over the human cytochrome <em>b</em> homologue. As a result, a highly selective and efficacious lead compound was identified. The combination of our lead compound with BNZ rapidly clears<em> T. cruzi</em> parasites, both <em>in vitro</em> and <em>in vivo</em>, and shows great potential to overcome key issues associated with currently available treatments.  </span></p>