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

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi,
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 in vivo 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 Qi active site of T. cruzi cytochrome
b, part of the cytochrome bc1 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 b homologue.
As a result, a highly selective and efficacious lead compound was
identified. The combination of our lead compound with BNZ rapidly clears
T. cruzi parasites, both in vitro and in vivo, and shows great potential
to overcome key issues associated with currently available
treatments.