Validation of Babesia proteasome as a drug target
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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-12-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320717301574 |
| _version_ | 1818766037779218432 |
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| author | Marie Jalovecka David Hartmann Yukiko Miyamoto Lars Eckmann Ondrej Hajdusek Anthony J. O'Donoghue Daniel Sojka |
| author_facet | Marie Jalovecka David Hartmann Yukiko Miyamoto Lars Eckmann Ondrej Hajdusek Anthony J. O'Donoghue Daniel Sojka |
| author_sort | Marie Jalovecka |
| collection | DOAJ |
| description | 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: Proteasome, Babesia, Carfilzomib, Epoxyketone, Cytotoxicity |
| first_indexed | 2024-12-18T08:27:37Z |
| format | Article |
| id | doaj.art-7aed7007bc3b4a1595d5b766bd2056b9 |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-12-18T08:27:37Z |
| publishDate | 2018-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-7aed7007bc3b4a1595d5b766bd2056b92022-12-21T21:14:34ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-12-0183394402Validation of Babesia proteasome as a drug targetMarie Jalovecka0David Hartmann1Yukiko Miyamoto2Lars Eckmann3Ondrej Hajdusek4Anthony J. O'Donoghue5Daniel Sojka6Institute 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 RepublicInstitute 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 RepublicDepartment of Medicine, University of California, San Diego, La Jolla, USADepartment of Medicine, University of California, San Diego, La Jolla, USAInstitute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-370 05, Ceske Budejovice, Czech RepublicSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, USA; Corresponding author. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, CA, 92093-0657, La Jolla, USA.Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-370 05, Ceske Budejovice, Czech Republic; Corresponding author.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: Proteasome, Babesia, Carfilzomib, Epoxyketone, Cytotoxicityhttp://www.sciencedirect.com/science/article/pii/S2211320717301574 |
| spellingShingle | Marie Jalovecka David Hartmann Yukiko Miyamoto Lars Eckmann Ondrej Hajdusek Anthony J. O'Donoghue Daniel Sojka Validation of Babesia proteasome as a drug target International Journal for Parasitology: Drugs and Drug Resistance |
| title | Validation of Babesia proteasome as a drug target |
| title_full | Validation of Babesia proteasome as a drug target |
| title_fullStr | Validation of Babesia proteasome as a drug target |
| title_full_unstemmed | Validation of Babesia proteasome as a drug target |
| title_short | Validation of Babesia proteasome as a drug target |
| title_sort | validation of babesia proteasome as a drug target |
| url | http://www.sciencedirect.com/science/article/pii/S2211320717301574 |
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