Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis
Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-par...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | International Journal for Parasitology: Drugs and Drug Resistance |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320723000106 |
| _version_ | 1797855271843790848 |
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| author | Roman Memedovski Matías Preza Joachim Müller Tobias Kämpfer Reto Rufener Marcus Vinicius Nora de Souza Emerson Teixeira da Silva Gabriel Fernandes de Andrade Sophie Braga Anne-Christine Uldry Natasha Buchs Manfred Heller Britta Lundström-Stadelmann |
| author_facet | Roman Memedovski Matías Preza Joachim Müller Tobias Kämpfer Reto Rufener Marcus Vinicius Nora de Souza Emerson Teixeira da Silva Gabriel Fernandes de Andrade Sophie Braga Anne-Christine Uldry Natasha Buchs Manfred Heller Britta Lundström-Stadelmann |
| author_sort | Roman Memedovski |
| collection | DOAJ |
| description | Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed.Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1′681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE. |
| first_indexed | 2024-04-09T20:21:02Z |
| format | Article |
| id | doaj.art-89a49aeeca2f46a99fa3bbefacf831fb |
| institution | Directory Open Access Journal |
| issn | 2211-3207 |
| language | English |
| last_indexed | 2024-04-09T20:21:02Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | International Journal for Parasitology: Drugs and Drug Resistance |
| spelling | doaj.art-89a49aeeca2f46a99fa3bbefacf831fb2023-03-31T05:53:23ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072023-04-0121114124Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularisRoman Memedovski0Matías Preza1Joachim Müller2Tobias Kämpfer3Reto Rufener4Marcus Vinicius Nora de Souza5Emerson Teixeira da Silva6Gabriel Fernandes de Andrade7Sophie Braga8Anne-Christine Uldry9Natasha Buchs10Manfred Heller11Britta Lundström-Stadelmann12Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandInstitute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandInstitute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandInstitute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandInstitute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, SwitzerlandFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos – Far Manguinhos, 21041-250, Rio de Janeiro, BrazilFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos – Far Manguinhos, 21041-250, Rio de Janeiro, BrazilFundação Oswaldo Cruz, Instituto de Tecnologia em Fármacos – Far Manguinhos, 21041-250, Rio de Janeiro, BrazilProteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandProteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandProteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandProteomics and Mass Spectrometry Core Facility, Department for BioMedical Research (DBMR), University of Bern, Bern, SwitzerlandInstitute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Bern, Switzerland; Multidisciplinary Center for Infectious Diseases, University of Bern, Bern, Switzerland; Corresponding author. Institute of Parasitology, Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, University of Bern, Switzerland.Alveolar echinococcosis (AE) is caused by infection with the fox tapeworm E. multilocularis. The disease affects humans, dogs, captive monkeys, and other mammals, and it is caused by the metacestode stage of the parasite growing invasively in the liver. The current drug treatment is based on non-parasiticidal benzimidazoles. Thus, they are only limitedly curative and can cause severe side effects. Therefore, novel and improved treatment options for AE are needed.Mefloquine (MEF), an antimalarial agent, was previously shown to be effective against E. multilocularis in vitro and in experimentally infected mice. However, MEF is not parasiticidal and needs improvement for successful treatment of patients, and it can induce strong neuropsychiatric side-effects. In this study, the structure-activity relationship and mode of action of MEF was investigated by comparative analysis of 14 MEF derivatives. None of them showed higher activity against E. multilocularis metacestodes compared to MEF, but four compounds caused limited damage. In order to identify molecular targets of MEF and effective derivatives, differential affinity chromatography combined with mass spectrometry was performed with two effective compounds (MEF, MEF-3) and two ineffective compounds (MEF-13, MEF-22). 1′681 proteins were identified that bound specifically to MEF or derivatives. 216 proteins were identified as binding only to MEF and MEF-3. GO term enrichment analysis of these proteins and functional grouping of the 25 most abundant MEF and MEF-3 specific binding proteins revealed the key processes energy metabolism and cellular transport and structure, as well as stress responses and nucleic acid binding to be involved. The previously described ferritin was confirmed as an exclusively MEF-binding protein that could be relevant for its efficacy against E. multilocularis. The here identified potential targets of MEF will be further investigated in the future for a clear understanding of the pleiotropic effects of MEF, and improved therapeutic options against AE.http://www.sciencedirect.com/science/article/pii/S2211320723000106Echinococcus multilocularisAlveolar echinococcosisMefloquineStructure-activity relationship (SAR)Mode of actionnLC-MS/MS |
| spellingShingle | Roman Memedovski Matías Preza Joachim Müller Tobias Kämpfer Reto Rufener Marcus Vinicius Nora de Souza Emerson Teixeira da Silva Gabriel Fernandes de Andrade Sophie Braga Anne-Christine Uldry Natasha Buchs Manfred Heller Britta Lundström-Stadelmann Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis International Journal for Parasitology: Drugs and Drug Resistance Echinococcus multilocularis Alveolar echinococcosis Mefloquine Structure-activity relationship (SAR) Mode of action nLC-MS/MS |
| title | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| title_full | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| title_fullStr | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| title_full_unstemmed | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| title_short | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| title_sort | investigation of the mechanism of action of mefloquine and derivatives against the parasite echinococcus multilocularis |
| topic | Echinococcus multilocularis Alveolar echinococcosis Mefloquine Structure-activity relationship (SAR) Mode of action nLC-MS/MS |
| url | http://www.sciencedirect.com/science/article/pii/S2211320723000106 |
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