Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas' Disease

Phenotypic screening identified an arylsulfonamide compound with activity against Trypanosoma cruzi, the causative agent of Chagas' disease. Comprehensive mode of action studies revealed that this compound primarily targets the T. cruzi proteasome, binding at the interface between beta 4 and beta 5 subunits that catalyze chymotrypsin-like activity. A mutation in the beta 5 subunit of the proteasome was associated with resistance to compound 1, while overexpression of this mutated subunit also reduced susceptibility to compound 1. Further genetically engineered and in vitro-selected clones resistant to proteasome inhibitors known to bind at the beta 4/beta 5 interface were cross-resistant to compound 1. Ubiquitinated proteins were additionally found to accumulate in compound 1-treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound 1, although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the T. cruzi proteasome that may be exploitable for anti-chagasic drug discovery.

Automated summary

Phenotypic screening has identified a potential compound for treating Chagas' disease caused by Trypanosoma cruzi. Further studies have revealed the compound's primary target and identified potential secondary targets. These findings provide new insights for the discovery of anti-Chagas drugs.