Evaluating Antimalarial Proteasome Inhibitors for Efficacy in Blood Stage Cultures.

Tick-transmitted are a major global veterinary threat and an emerging risk to humans. Unlike their relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the proteasome holds promise for drug development. In this study, we screened a library of peptide epoxyketone inhibitors derived from the marine natural product carmaphycin B for their activity against . Several of these compounds showed activity against both the asexual and sexual blood stages of . These compounds inactivate β5 proteasome subunit activity in the lysates of and in the low nanomolar range. Several compounds were tested with the purified proteasome and showed IC values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited growth in bovine erythrocyte cultures with solid EC values, but importantly, they appeared less toxic to human cells than carfilzomib. These compounds therefore offer a wider therapeutic window and provide new insights into the development of small proteasome inhibitors as selective drugs for babesiosis.