Identification of a proteasome-targeting arylsulfonamide with potential for the treatment of Chagas' disease
AUTHORS
- PMID: 34606338 [PubMed].
ABSTRACT
Phenotypic screening identified an arylsulfonamide compound with activity against , the causative agent of Chagas’ disease. Comprehensive mode of action studies revealed that this compound primarily targets the proteasome, binding at the interface between β4 and β5 subunits that catalyse chymotrypsin-like activity. A mutation in the β5 subunit of the proteasome was associated with resistance to compound , while overexpression of this mutated subunit also reduced susceptibility to compound . Further genetically engineered and selected clones resistant to proteasome inhibitors known to bind at the β4/β5 interface were cross-resistant to compound . Ubiquitinylated proteins were additionally found to accumulate in compound -treated epimastigotes. Finally, thermal proteome profiling identified malic enzyme as a secondary target of compound , although malic enzyme inhibition was not found to drive potency. These studies identify a novel pharmacophore capable of inhibiting the proteasome that may be exploitable for anti-chagasic drug discovery.
Tags: alumni publications 2021