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Int J Parasitol Drugs Drug Resist. 2018 Dec;8(3):394-402. doi: 10.1016/j.ijpddr.2018.08.001. Epub 2018 Aug 7.

Validation of Babesia proteasome as a drug target.

Author information

1
Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-370 05, Ceske Budejovice, Czech Republic; Faculty of Science, University of South Bohemia, CZ-370 05, Ceske Budejovice, Czech Republic.
2
Department of Medicine, University of California, San Diego, La Jolla, USA.
3
Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-370 05, Ceske Budejovice, Czech Republic.
4
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, USA. Electronic address: ajodonoghue@ucsd.edu.
5
Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-370 05, Ceske Budejovice, Czech Republic. Electronic address: sojkadan@gmail.com.

Abstract

Babesiosis is a tick-transmitted zoonosis caused by apicomplexan parasites of the genus Babesia. Treatment of this emerging malaria-related disease has relied on antimalarial drugs and antibiotics. The proteasome of Plasmodium, the causative agent of malaria, has recently been validated as a target for anti-malarial drug development and therefore, in this study, we investigated the effect of epoxyketone (carfilzomib, ONX-0914 and epoxomicin) and boronic acid (bortezomib and ixazomib) proteasome inhibitors on the growth and survival of Babesia. Testing the compounds against Babesia divergens ex vivo revealed suppressive effects on parasite growth with activity that was higher than the cytotoxic effects on a non-transformed mouse macrophage cell line. Furthermore, we showed that the most-effective compound, carfilzomib, significantly reduces parasite multiplication in a Babesia microti infected mouse model without noticeable adverse effects. In addition, treatment with carfilzomib lead to an ex vivo and in vivo decrease in proteasome activity and accumulation of polyubiquitinated proteins compared to untreated control. Overall, our results demonstrate that the Babesia proteasome is a valid target for drug development and warrants the design of potent and selective B. divergens proteasome inhibitors for the treatment of babesiosis.

KEYWORDS:

Babesia; Carfilzomib; Cytotoxicity; Epoxyketone; Proteasome

PMID:
30103207
PMCID:
PMC6092455
DOI:
10.1016/j.ijpddr.2018.08.001
[Indexed for MEDLINE]
Free PMC Article

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