Carmaphycin B-Based Proteasome Inhibitors to Treat Human African Trypanosomiasis: Structure-Activity Relationship and <i>In Vivo</i> Efficacy.

ABSTRACT: The proteasome is essential for eukaryotic cell proteostasis, and inhibitors of the 20S proteasome are progressing preclinically and clinically as antiparasitics. We screenedTrypanosoma brucei, the causative agent of human and animal African trypanosomiasis, in vitro with a set of 27 carmaphycin B analogs, irreversible epoxyketone inhibitors that were originally developed to inhibit thePlasmodium falciparum20S (Pf20S). The structure-activity relationship was distinct from that of the human c20S antitarget by the acceptance of d-amino acids at the P3 position of the peptidyl backbone to yield compounds with greatly decreased toxicity to human cells. For the three most selective compounds, binding to the Tb20S β5 catalytic subunit was confirmed by competition with a fluo

SUBMITTER: Liu LJ 

PROVIDER: S-EPMC11650654 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature