Abstract
Using high throughput, high-content imaging, a proprietary library was screened against intracellular Trypanosoma cruzi amastigotes to identify compounds with novel activity against the parasite. Five inhibitors were discovered, which did not clear all of the parasites from 3T3 host cells following 48 hours exposure, and were identified as putative T. cruzi cytochrome P450 (TcCYP51) inhibitors. TcCYP51 inhibitors are not favourable for the drug discovery pipeline for treatment of Chagas Disease infection due to clinical and pre-clinical failures. To determine if there were in vitro inhibitory characteristics of these compounds that could aid the prediction of TcCYP51 inhibition further profiling using imaging and fluorescence based assays was undertaken. It was determined that in vitro profiles, coupled with analysis of chemical structure, could support the early prediction of putative TcCYP51 activity and thus enable early de-prioritisation of these compounds from progression through the drug discovery pipeline.
Highlights
Chagas disease, caused by Trypanosoma cruzi is responsible for around 14 000 deaths per year, with a further 6–8 million people effected by the disease[1]
Clemastine fumarate (CF), identified by us and other researchers to be active against T. cruzi[5,10], with an unknown mode of action (MOA), was tested to determine if CF was active against recombinant TcCYP51
CYP51 was considered to be an important target in T. cruzi for some time because of the potency demonstrated in vitro by a number of CYP51 inhibitors, and suppression exhibited in vivo[12,13,16,23]
Summary
Chagas disease, caused by Trypanosoma cruzi is responsible for around 14 000 deaths per year, with a further 6–8 million people effected by the disease[1]. There are two current drugs, benznidazole (BZ) and nifurtimox (NFX), used to treat infection with this parasite, which require complicated and lengthy dosing regimens and present associated side effects which compromise compliance[2,3]. These drugs have questionable efficacy, associated with the chronic phase of the disease[4]. The phenotypic characteristics of T. cruzi infected cells following 48 hours treatment with these hit compounds strongly supported the prediction that a sub-efficacious effect was common to TcCYP51 inhibitors.
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