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Validation of Babesia proteasome as a drug target
M. Jalovecka, D. Hartmann, Y. Miyamoto, L. Eckmann, O. Hajdusek, AJ. O'Donoghue, D. Sojka,
Language English Country England, Great Britain
Document type Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study
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- MeSH
- Babesia microti drug effects genetics growth & development MeSH
- Babesia drug effects genetics growth & development MeSH
- Babesiosis drug therapy MeSH
- Cell Line MeSH
- Proteasome Inhibitors administration & dosage adverse effects pharmacology therapeutic use MeSH
- Boronic Acids pharmacology MeSH
- Drug Delivery Systems * MeSH
- Macrophages drug effects parasitology MeSH
- Disease Models, Animal MeSH
- Mice MeSH
- Oligopeptides pharmacology MeSH
- Proteasome Endopeptidase Complex drug effects MeSH
- Proteome drug effects genetics MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Research Support, N.I.H., Extramural MeSH
- Validation Study MeSH
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.
Department of Medicine University of California San Diego La Jolla USA
Faculty of Science University of South Bohemia CZ 370 05 Ceske Budejovice Czech Republic
References provided by Crossref.org
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- $a 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.
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