Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis
Resumen:
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 MEFbinding 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.
| 2023 | |
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Echinococcus multilocularis Alveolar echinococcosis Mefloquine Structure-activity relationship (SAR) Mode of action nLC-MS/MS Ferritin Energy metabolism |
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| Inglés | |
| Universidad de la República | |
| COLIBRI | |
| https://hdl.handle.net/20.500.12008/43164 | |
| Acceso abierto | |
| Licencia Creative Commons Atribución (CC - By 4.0) |
| _version_ | 1807522807774445568 |
|---|---|
| author | Memedovski, Roman |
| author2 | Preza Pérez, Matías Facundo Müller, Joachim Kampfer, Tobias Rufener, Reto Nora de Souza, Marcus Vinicius Teixeira da Silva, Emerson Fernandes de Andrade, Gabriel Braga, Sophie Uldry, Anne-Christine Buchs, Natasha Heller, Manfred Lundström-Stadelmann, Britta |
| author2_role | author author author author author author author author author author author author |
| author_facet | Memedovski, Roman Preza Pérez, Matías Facundo Müller, Joachim Kampfer, Tobias Rufener, Reto Nora de Souza, Marcus Vinicius Teixeira da Silva, Emerson Fernandes de Andrade, Gabriel Braga, Sophie Uldry, Anne-Christine Buchs, Natasha Heller, Manfred Lundström-Stadelmann, Britta |
| author_role | author |
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| collection | COLIBRI |
| dc.contributor.filiacion.none.fl_str_mv | Memedovski Roman Preza Pérez Matías Facundo, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Biología. Müller Joachim Kampfer Tobias Rufener Reto Nora de Souza Marcus Vinicius Teixeira da Silva Emerson Fernandes de Andrade Gabriel Braga Sophie Uldry Anne-Christine Buchs Natasha Heller Manfred Lundström-Stadelmann Britta |
| dc.creator.none.fl_str_mv | Memedovski, Roman Preza Pérez, Matías Facundo Müller, Joachim Kampfer, Tobias Rufener, Reto Nora de Souza, Marcus Vinicius Teixeira da Silva, Emerson Fernandes de Andrade, Gabriel Braga, Sophie Uldry, Anne-Christine Buchs, Natasha Heller, Manfred Lundström-Stadelmann, Britta |
| dc.date.accessioned.none.fl_str_mv | 2024-03-19T12:13:34Z |
| dc.date.available.none.fl_str_mv | 2024-03-19T12:13:34Z |
| dc.date.issued.none.fl_str_mv | 2023 |
| dc.description.abstract.none.fl_txt_mv | 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 MEFbinding 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. |
| dc.format.extent.es.fl_str_mv | 11 h. |
| dc.format.mimetype.es.fl_str_mv | application/pdf |
| dc.identifier.citation.es.fl_str_mv | Memedovski, R, Preza Pérez, M, Müller, J [y otros autores]. "Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis". International Journal for Parasitology: Drugs and Drug Resistance. [en línea] 2023, 21: 114-124. 11 h. DOI: 10.1016/j.ijpddr.2023.03.002. |
| dc.identifier.doi.none.fl_str_mv | 10.1016/j.ijpddr.2023.03.002 |
| dc.identifier.issn.none.fl_str_mv | 2211-3207 |
| dc.identifier.uri.none.fl_str_mv | https://hdl.handle.net/20.500.12008/43164 |
| dc.language.iso.none.fl_str_mv | en eng |
| dc.publisher.es.fl_str_mv | Elsevier |
| dc.relation.ispartof.es.fl_str_mv | International Journal for Parasitology: Drugs and Drug Resistance, 2023, 21: 114-124. |
| dc.rights.license.none.fl_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
| dc.rights.none.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.source.none.fl_str_mv | reponame:COLIBRI instname:Universidad de la República instacron:Universidad de la República |
| dc.subject.es.fl_str_mv | Echinococcus multilocularis Alveolar echinococcosis Mefloquine Structure-activity relationship (SAR) Mode of action nLC-MS/MS Ferritin Energy metabolism |
| dc.title.none.fl_str_mv | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis |
| dc.type.es.fl_str_mv | Artículo |
| dc.type.none.fl_str_mv | info:eu-repo/semantics/article |
| dc.type.version.none.fl_str_mv | info:eu-repo/semantics/publishedVersion |
| 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 MEFbinding 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | COLIBRI_66a7a3c8853028ca7933d63a158499d2 |
| identifier_str_mv | Memedovski, R, Preza Pérez, M, Müller, J [y otros autores]. "Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis". International Journal for Parasitology: Drugs and Drug Resistance. [en línea] 2023, 21: 114-124. 11 h. DOI: 10.1016/j.ijpddr.2023.03.002. 2211-3207 10.1016/j.ijpddr.2023.03.002 |
| instacron_str | Universidad de la República |
| institution | Universidad de la República |
| instname_str | Universidad de la República |
| language | eng |
| language_invalid_str_mv | en |
| network_acronym_str | COLIBRI |
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| oai_identifier_str | oai:colibri.udelar.edu.uy:20.500.12008/43164 |
| publishDate | 2023 |
| reponame_str | COLIBRI |
| repository.mail.fl_str_mv | mabel.seroubian@seciu.edu.uy |
| repository.name.fl_str_mv | COLIBRI - Universidad de la República |
| repository_id_str | 4771 |
| rights_invalid_str_mv | Licencia Creative Commons Atribución (CC - By 4.0) |
| spelling | Memedovski RomanPreza Pérez Matías Facundo, Universidad de la República (Uruguay). Facultad de Ciencias. Instituto de Biología.Müller JoachimKampfer TobiasRufener RetoNora de Souza Marcus ViniciusTeixeira da Silva EmersonFernandes de Andrade GabrielBraga SophieUldry Anne-ChristineBuchs NatashaHeller ManfredLundström-Stadelmann Britta2024-03-19T12:13:34Z2024-03-19T12:13:34Z2023Memedovski, R, Preza Pérez, M, Müller, J [y otros autores]. "Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis". International Journal for Parasitology: Drugs and Drug Resistance. [en línea] 2023, 21: 114-124. 11 h. DOI: 10.1016/j.ijpddr.2023.03.002.2211-3207https://hdl.handle.net/20.500.12008/4316410.1016/j.ijpddr.2023.03.002Alveolar 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 MEFbinding 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.Submitted by Pintos Natalia (nataliapintosmvd@gmail.com) on 2024-03-15T16:33:22Z No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1016.j.ijpddr.2023.03.002.pdf: 4634109 bytes, checksum: d345e6762450ec613135ab1cff95dc9f (MD5)Approved for entry into archive by Faget Cecilia (lfaget@fcien.edu.uy) on 2024-03-19T12:07:51Z (GMT) No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1016.j.ijpddr.2023.03.002.pdf: 4634109 bytes, checksum: d345e6762450ec613135ab1cff95dc9f (MD5)Made available in DSpace by Luna Fabiana (fabiana.luna@seciu.edu.uy) on 2024-03-19T12:13:34Z (GMT). No. of bitstreams: 2 license_rdf: 24251 bytes, checksum: 71ed42ef0a0b648670f707320be37b90 (MD5) 10.1016.j.ijpddr.2023.03.002.pdf: 4634109 bytes, checksum: d345e6762450ec613135ab1cff95dc9f (MD5) Previous issue date: 202311 h.application/pdfenengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance, 2023, 21: 114-124.Las obras depositadas en el Repositorio se rigen por la Ordenanza de los Derechos de la Propiedad Intelectual de la Universidad de la República.(Res. Nº 91 de C.D.C. de 8/III/1994 – D.O. 7/IV/1994) y por la Ordenanza del Repositorio Abierto de la Universidad de la República (Res. Nº 16 de C.D.C. de 07/10/2014)info:eu-repo/semantics/openAccessLicencia Creative Commons Atribución (CC - By 4.0)Echinococcus multilocularisAlveolar echinococcosisMefloquineStructure-activity relationship (SAR)Mode of actionnLC-MS/MSFerritinEnergy metabolismInvestigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularisArtículoinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionreponame:COLIBRIinstname:Universidad de la Repúblicainstacron:Universidad de la RepúblicaMemedovski, RomanPreza Pérez, Matías FacundoMüller, JoachimKampfer, TobiasRufener, RetoNora de Souza, Marcus ViniciusTeixeira da Silva, EmersonFernandes de Andrade, GabrielBraga, SophieUldry, Anne-ChristineBuchs, NatashaHeller, ManfredLundström-Stadelmann, BrittaLICENSElicense.txtlicense.txttext/plain; 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- Universidad de la Repúblicafalse |
| spellingShingle | Investigation of the mechanism of action of mefloquine and derivatives against the parasite Echinococcus multilocularis Memedovski, Roman Echinococcus multilocularis Alveolar echinococcosis Mefloquine Structure-activity relationship (SAR) Mode of action nLC-MS/MS Ferritin Energy metabolism |
| status_str | publishedVersion |
| 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 Ferritin Energy metabolism |
| url | https://hdl.handle.net/20.500.12008/43164 |
