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Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis.
Int J Parasitol Drugs Drug Resist. 2018 12; 8(3):440-450.IJ

Abstract

The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti-theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 μM and 0.02 μM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity.

Authors+Show Affiliations

Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Laboratory of Medical and Molecular Parasitology-Mycology, LR 12ES08, Department of Clinical Biology B, Faculty of Pharmacy of Monastir, University of Monastir, Monastir, 5000, Tunisia.Medicines for Malaria Venture (MMV), Route de Pré-Bois 20, 1215, Geneva, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland.Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggassstrasse 122, 3012, Bern, Switzerland. Electronic address: Britta.lundstroem@vetsuisse.unibe.ch.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30396011

Citation

Rufener, Reto, et al. "Repurposing of an Old Drug: in Vitro and in Vivo Efficacies of Buparvaquone Against Echinococcus Multilocularis." International Journal for Parasitology. Drugs and Drug Resistance, vol. 8, no. 3, 2018, pp. 440-450.
Rufener R, Dick L, D'Ascoli L, et al. Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. Int J Parasitol Drugs Drug Resist. 2018;8(3):440-450.
Rufener, R., Dick, L., D'Ascoli, L., Ritler, D., Hizem, A., Wells, T. N. C., Hemphill, A., & Lundström-Stadelmann, B. (2018). Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. International Journal for Parasitology. Drugs and Drug Resistance, 8(3), 440-450. https://doi.org/10.1016/j.ijpddr.2018.10.011
Rufener R, et al. Repurposing of an Old Drug: in Vitro and in Vivo Efficacies of Buparvaquone Against Echinococcus Multilocularis. Int J Parasitol Drugs Drug Resist. 2018;8(3):440-450. PubMed PMID: 30396011.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Repurposing of an old drug: In vitro and in vivo efficacies of buparvaquone against Echinococcus multilocularis. AU - Rufener,Reto, AU - Dick,Luca, AU - D'Ascoli,Laura, AU - Ritler,Dominic, AU - Hizem,Amani, AU - Wells,Timothy N C, AU - Hemphill,Andrew, AU - Lundström-Stadelmann,Britta, Y1 - 2018/10/31/ PY - 2018/08/10/received PY - 2018/10/29/revised PY - 2018/10/29/accepted PY - 2018/11/6/pubmed PY - 2019/1/31/medline PY - 2018/11/6/entrez KW - Cytochrome bc(1) complex KW - Drug screening KW - MMV671636 KW - MMV689480 KW - Pathogen box KW - Seahorse XFp analyzer SP - 440 EP - 450 JF - International journal for parasitology. Drugs and drug resistance JO - Int J Parasitol Drugs Drug Resist VL - 8 IS - 3 N2 - The metacestode stage of the fox tapeworm Echinococcus multilocularis causes the lethal disease alveolar echinococcosis. Current chemotherapeutic treatment options are based on benzimidazoles (albendazole and mebendazole), which are insufficient and hence alternative drugs are needed. In this study, we screened the 400 compounds of the Medicines for Malaria Venture (MMV) Pathogen Box against E. multilocularis metacestodes. For the screen, we employed the phosphoglucose isomerase (PGI) assay which assesses drug-induced damage on metacestodes, and identified ten new compounds with activity against the parasite. The anti-theilerial drug MMV689480 (buparvaquone) and MMV671636 (ELQ-400) were the most promising compounds, with an IC50 of 2.87 μM and 0.02 μM respectively against in vitro cultured E. multilocularis metacestodes. Both drugs suggested a therapeutic window based on their cytotoxicity against mammalian cells. Transmission electron microscopy revealed that treatment with buparvaquone impaired parasite mitochondria early on and additional tests showed that buparvaquone had a reduced activity under anaerobic conditions. Furthermore, we established a system to assess mitochondrial respiration in isolated E. multilocularis cells in real time using the Seahorse XFp Analyzer and demonstrated inhibition of the cytochrome bc1 complex by buparvaquone. Mice with secondary alveolar echinococcosis were treated with buparvaquone (100 mg/kg per dose, three doses per week, four weeks of treatment), but the drug failed to reduce the parasite burden in vivo. Future studies will reveal whether improved formulations of buparvaquone could increase its effectivity. SN - 2211-3207 UR - https://www.unboundmedicine.com/medline/citation/30396011/Repurposing_of_an_old_drug:_In_vitro_and_in_vivo_efficacies_of_buparvaquone_against_Echinococcus_multilocularis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2211-3207(18)30122-2 DB - PRIME DP - Unbound Medicine ER -