Identification of a Proteasome-Targeting Arylsulfonamide with Potential for the Treatment of Chagas’ Disease
Marta Lopes Lima, L.B. Tulloch, Victoriano Corpas‐López, Sandra Carvalho, Richard J. Wall, Rachel Milne, Eva Rico, Stephen Patterson, Ian H. Gilbert, Sónia Moniz, Lorna MacLean, Leah S. Torrie, Carmine Marco Morgillo, David Horn, Fabio Zuccotto, Susan Wyllie
Abstract
-selected clones resistant to proteasome inhibitors known to bind at the β4/β5 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.