Pharmacological and structural understanding of the Trypanosoma cruzi proteasome provides key insights for developing site-specific inhibitors.

ABSTRACT: The proteasome is considered an excellent drug target for many infectious diseases as well as cancer. Challenges with robust and safe supply of proteasomes from infectious agents, lack of structural information, and complex pharmacology due to multiple active sites have hampered progress in the infectious disease space. We recombinantly expressed the proteasome of the protozoan parasite Trypanosoma cruzi, the causative agent of Chagas disease, and demonstrate pharmacological equivalence to the native T. cruzi proteasome. Active-site mutant recombinant proteasomes reveal substrate promiscuity for WT proteasomes, with important implications for assessing pharmacological responses of active-site selective inhibitors. Using these mutant proteasomes, we show that some selective parasite proteas

SUBMITTER: Eadsforth TC 

PROVIDER: S-EPMC11748689 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature