Identification of a proteasome-targeting arylsulfonamide with potential for the treatment of Chagas' disease

Marta Lima, Lindsay Tulloch, Victoriano Corpas Lopez, Sandra Carvalho, Richard Wall, Rachel Milne, Eva Rico Vidal, Stephen Patterson, Ian Gilbert, Sonia Moniz, Lorna MacLean, Leah Torrie, Carmine Morgillo, David Horn, Fabio Zuccotto, Susan Wyllie (Lead / Corresponding author)

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Abstract

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 β4 and β5 subunits that catalyse chymotrypsin-like activity. A mutation in the β5 subunit 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 β4/β5 interface were cross-resistant to compound 1. Ubiquitinylated 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.
Original languageEnglish
Article numbere01535-21
Number of pages16
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number1
Early online date4 Oct 2021
DOIs
Publication statusPublished - 18 Jan 2022

Keywords

  • Chagas disease
  • drug discovery
  • proteasome,
  • malic enzyme
  • drug target
  • mechanism of action
  • Drug target
  • Chagas' disease
  • Drug discovery
  • Mechanism of action
  • Malic enzyme
  • Proteasome

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