Tick-transmitted Babesia are a major global veterinary threat and an emerging risk to humans. Unlike their Plasmodium relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the Babesia 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 Babesia. Several of these compounds showed activity against both the asexual and sexual blood stages of Plasmodium falciparum. These compounds inactivate β5 proteasome subunit activity in the lysates of Babesia divergens and Babesia microti in the low nanomolar range. Several compounds were tested with the purified B. divergens proteasome and showed IC50 values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited B. divergens growth in bovine erythrocyte cultures with solid EC50 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.

Center for Marine Biotechnology and Biomedicine Scripps Institution of Oceanography University of California San Diego San Diego La Jolla California 92093 0212 United States

Faculty of Science University of South Bohemia Ceske Budejovice 370 05 Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic Prague 117 20 Czech Republic

Institute of Parasitology Biology Centre of the Czech Academy of Sciences Ceske Budejovice 370 05 Czech Republic

Skaggs School of Pharmacy and Pharmaceutical Sciences University of California San Diego San Diego La Jolla California 92093 0755 United States

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Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome

Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome