Evaluating Antimalarial Proteasome Inhibitors for Efficacy in <i>Babesia</i> Blood Stage Cultures
Tick-transmitted <i>Babesia</i> are a major global veterinary threat and an emerging risk to humans. Unlike their <i>Plasmodium</i> relatives, these erythrocyte-infecting Apicomplexa have been largely overlooked and lack specific treatment. Selective targeting of the <i>Babesia</i> 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 <i>Babesia</i>. Several of these compounds showed activity against both the asexual and sexual blood stages of <i>Plasmodium falciparum</i>. These compounds inactivate β5 proteasome subunit activity in the lysates of <i>Babesia divergens</i> and <i>Babesia microti</i> in the low nanomolar range. Several compounds were tested with the purified <i>B. divergens</i> proteasome and showed IC<sub>50</sub> values comparable to carfilzomib, an approved anticancer proteasome inhibitor. They also inhibited <i>B. divergens</i> growth in bovine erythrocyte cultures with solid EC<sub>50</sub> 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.
Authors
- Momen Al-Hindy (ORCID: https://orcid.org/0009-0008-5302-642X)
- Petr Pachl (ORCID: https://orcid.org/0000-0001-9215-9817)
- Elany Barbosa da Silva (ORCID: https://orcid.org/0000-0002-1926-3500)
- Pavla Fajtová (ORCID: https://orcid.org/0000-0002-4029-0706)
- Luïse Robbertse (ORCID: https://orcid.org/0000-0002-3961-8241)
- Pavla Šnebergerová (ORCID: https://orcid.org/0000-0003-3277-7001)
- Anthony J. O’Donoghue (ORCID: https://orcid.org/0000-0001-5695-0409)
- Daniel Sojka (ORCID: https://orcid.org/0000-0002-9848-9435)
- V. A. Levytska (ORCID: https://orcid.org/0000-0003-3100-009X)
- Evžen Bouřa (ORCID: https://orcid.org/0000-0002-9652-4065)
- Jehad Almaliti (ORCID: https://orcid.org/0000-0002-3562-0846)
- William H. Gerwick (ORCID: https://orcid.org/0000-0003-1403-4458)
- Marie Jalovecká (ORCID: https://orcid.org/0000-0003-4681-116X)
- Vandna Sharma (ORCID: https://orcid.org/0000-0002-3054-2658)
Institutions
- Scripps Institution of Oceanography (US)
- University of South Bohemia in České Budějovice (CZ)
- University of California San Diego (US)
- Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry (CZ)
- Institute of Parasitology (CZ)
- Czech Academy of Sciences, Biology Centre (CZ)
- University of Montana (US)
Publication Details
- Journal
- ACS Omega
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1021/acsomega.4c04564
- Citations
- 6
- Primary Topic
- Vector-borne infectious diseases
- Type
- article
- Field-Weighted Citation Impact
- 3.09
Funders
- Bill and Melinda Gates Foundation
- European Cooperation in Science and Technology
- Grantová Agentura České Republiky
- National Institutes of Health
- H2020 Marie Skłodowska-Curie Actions