Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model

Autores
Monteiro Guedes, Marina; Camargo de Lima, Jeferson; Andrade Paes, Jéssica; Cevasco Contreras, María del Pilar; Celentano Stanic, Ana Maria Luisa Micaela; Zaha, Arnaldo; Monteiro, Karina Mariante; Rosenzvit, Mara Cecilia; Bunselmeyer Ferreira, Henrique
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Cestodiases, like echinococcoses and cysticercoses, represent a global health problem. Currently available anthelmintics, as benzimidazoles and praziquantel, have limited effectiveness against these cestodiases, creating a demand for the identification of new and more effective drugs. Here, the potential of statins (simvastatin and fluvastatin), for repositioning as novel anthelmintic is explored. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a main enzyme in the mevalonate pathway, which is vital for the synthesis of non-steroidal isoprenoids and the maintenance of normal cell functioning. A survey for HMG-CoA reductase encoding genes showed that they are present in a single copy in the genomes of parasitic helminths and their mammal hosts. Sequence alignments and phylogenetic analyses showed 20?95% overall identities among ortholog HMG-CoA reductases, with special conservation of their catalytic domains. The HMG-CoA reductase 3D-structure was predicted for orthologs from 3 cestodes of medical importance (Echinococcus multilocularis, Echinococcus granulosus sensu lato, and Taenia solium), and from a model cestode species (Mesocestoides corti). Molecular docking between cestode HMG-CoA reductase orthologs with simvastatin demonstrated that the Arg, Ser, Lys, and Glu residues in conserved positions of the active site interact with this drug, similarly to the interactions predicted for the human reference ortholog enzyme. Furthermore, in vitro assays demonstrated that simvastatin produced a significant reduction of M. corti viability, being able to reduce 100% of parasite viability at 150 μm. Fluvastatin was also assessed showing a lower, although significant anthelmintic effect. The predicted overall structures and interactions together with in vitro assays suggest that cestodes HMG-CoA reductases are inhibited by simvastatin, being a potential therapeutic target for the repurposing of simvastatin as anthelmintic drug. Furthermore, these results pave the way for the in vivo evaluation of the potential effects of simvastatin on cestode larvae.
Fil: Monteiro Guedes, Marina. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Camargo de Lima, Jeferson. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Andrade Paes, Jéssica. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Cevasco Contreras, María del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Celentano Stanic, Ana Maria Luisa Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Zaha, Arnaldo. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Monteiro, Karina Mariante. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Bunselmeyer Ferreira, Henrique. Universidade Federal do Rio Grande do Sul; Brasil
Materia
Echinococcus granulosus
Echinococcus multilocularis
Mesocestoides corti
Mevalonate pathway
Taenia solium
drug repurposing
statins
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/266247
Acceder
id CONICETDig_2b764927b2156fbf2a944cfa793d6e20
oai_identifier_str oai:ri.conicet.gov.ar:11336/266247
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode modelMonteiro Guedes, MarinaCamargo de Lima, JefersonAndrade Paes, JéssicaCevasco Contreras, María del PilarCelentano Stanic, Ana Maria Luisa MicaelaZaha, ArnaldoMonteiro, Karina MarianteRosenzvit, Mara CeciliaBunselmeyer Ferreira, HenriqueEchinococcus granulosusEchinococcus multilocularisMesocestoides cortiMevalonate pathwayTaenia soliumdrug repurposingstatinshttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3Cestodiases, like echinococcoses and cysticercoses, represent a global health problem. Currently available anthelmintics, as benzimidazoles and praziquantel, have limited effectiveness against these cestodiases, creating a demand for the identification of new and more effective drugs. Here, the potential of statins (simvastatin and fluvastatin), for repositioning as novel anthelmintic is explored. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a main enzyme in the mevalonate pathway, which is vital for the synthesis of non-steroidal isoprenoids and the maintenance of normal cell functioning. A survey for HMG-CoA reductase encoding genes showed that they are present in a single copy in the genomes of parasitic helminths and their mammal hosts. Sequence alignments and phylogenetic analyses showed 20?95% overall identities among ortholog HMG-CoA reductases, with special conservation of their catalytic domains. The HMG-CoA reductase 3D-structure was predicted for orthologs from 3 cestodes of medical importance (Echinococcus multilocularis, Echinococcus granulosus sensu lato, and Taenia solium), and from a model cestode species (Mesocestoides corti). Molecular docking between cestode HMG-CoA reductase orthologs with simvastatin demonstrated that the Arg, Ser, Lys, and Glu residues in conserved positions of the active site interact with this drug, similarly to the interactions predicted for the human reference ortholog enzyme. Furthermore, in vitro assays demonstrated that simvastatin produced a significant reduction of M. corti viability, being able to reduce 100% of parasite viability at 150 μm. Fluvastatin was also assessed showing a lower, although significant anthelmintic effect. The predicted overall structures and interactions together with in vitro assays suggest that cestodes HMG-CoA reductases are inhibited by simvastatin, being a potential therapeutic target for the repurposing of simvastatin as anthelmintic drug. Furthermore, these results pave the way for the in vivo evaluation of the potential effects of simvastatin on cestode larvae.Fil: Monteiro Guedes, Marina. Universidade Federal do Rio Grande do Sul; BrasilFil: Camargo de Lima, Jeferson. Universidade Federal do Rio Grande do Sul; BrasilFil: Andrade Paes, Jéssica. Universidade Federal do Rio Grande do Sul; BrasilFil: Cevasco Contreras, María del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Celentano Stanic, Ana Maria Luisa Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Zaha, Arnaldo. Universidade Federal do Rio Grande do Sul; BrasilFil: Monteiro, Karina Mariante. Universidade Federal do Rio Grande do Sul; BrasilFil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Bunselmeyer Ferreira, Henrique. Universidade Federal do Rio Grande do Sul; BrasilCambridge University Press2024-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/266247Monteiro Guedes, Marina; Camargo de Lima, Jeferson; Andrade Paes, Jéssica; Cevasco Contreras, María del Pilar; Celentano Stanic, Ana Maria Luisa Micaela; et al.; Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model; Cambridge University Press; Parasitology; 13; 12-2024; 1-110031-1820CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.cambridge.org/core/product/identifier/S0031182024001586/type/journal_articleinfo:eu-repo/semantics/altIdentifier/doi/10.1017/S0031182024001586info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:43:10Zoai:ri.conicet.gov.ar:11336/266247instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:43:10.809CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
title Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
spellingShingle Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
Monteiro Guedes, Marina
Echinococcus granulosus
Echinococcus multilocularis
Mesocestoides corti
Mevalonate pathway
Taenia solium
drug repurposing
statins
title_short Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
title_full Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
title_fullStr Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
title_full_unstemmed Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
title_sort Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model
dc.creator.none.fl_str_mv Monteiro Guedes, Marina
Camargo de Lima, Jeferson
Andrade Paes, Jéssica
Cevasco Contreras, María del Pilar
Celentano Stanic, Ana Maria Luisa Micaela
Zaha, Arnaldo
Monteiro, Karina Mariante
Rosenzvit, Mara Cecilia
Bunselmeyer Ferreira, Henrique
author Monteiro Guedes, Marina
author_facet Monteiro Guedes, Marina
Camargo de Lima, Jeferson
Andrade Paes, Jéssica
Cevasco Contreras, María del Pilar
Celentano Stanic, Ana Maria Luisa Micaela
Zaha, Arnaldo
Monteiro, Karina Mariante
Rosenzvit, Mara Cecilia
Bunselmeyer Ferreira, Henrique
author_role author
author2 Camargo de Lima, Jeferson
Andrade Paes, Jéssica
Cevasco Contreras, María del Pilar
Celentano Stanic, Ana Maria Luisa Micaela
Zaha, Arnaldo
Monteiro, Karina Mariante
Rosenzvit, Mara Cecilia
Bunselmeyer Ferreira, Henrique
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Echinococcus granulosus
Echinococcus multilocularis
Mesocestoides corti
Mevalonate pathway
Taenia solium
drug repurposing
statins
topic Echinococcus granulosus
Echinococcus multilocularis
Mesocestoides corti
Mevalonate pathway
Taenia solium
drug repurposing
statins
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Cestodiases, like echinococcoses and cysticercoses, represent a global health problem. Currently available anthelmintics, as benzimidazoles and praziquantel, have limited effectiveness against these cestodiases, creating a demand for the identification of new and more effective drugs. Here, the potential of statins (simvastatin and fluvastatin), for repositioning as novel anthelmintic is explored. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a main enzyme in the mevalonate pathway, which is vital for the synthesis of non-steroidal isoprenoids and the maintenance of normal cell functioning. A survey for HMG-CoA reductase encoding genes showed that they are present in a single copy in the genomes of parasitic helminths and their mammal hosts. Sequence alignments and phylogenetic analyses showed 20?95% overall identities among ortholog HMG-CoA reductases, with special conservation of their catalytic domains. The HMG-CoA reductase 3D-structure was predicted for orthologs from 3 cestodes of medical importance (Echinococcus multilocularis, Echinococcus granulosus sensu lato, and Taenia solium), and from a model cestode species (Mesocestoides corti). Molecular docking between cestode HMG-CoA reductase orthologs with simvastatin demonstrated that the Arg, Ser, Lys, and Glu residues in conserved positions of the active site interact with this drug, similarly to the interactions predicted for the human reference ortholog enzyme. Furthermore, in vitro assays demonstrated that simvastatin produced a significant reduction of M. corti viability, being able to reduce 100% of parasite viability at 150 μm. Fluvastatin was also assessed showing a lower, although significant anthelmintic effect. The predicted overall structures and interactions together with in vitro assays suggest that cestodes HMG-CoA reductases are inhibited by simvastatin, being a potential therapeutic target for the repurposing of simvastatin as anthelmintic drug. Furthermore, these results pave the way for the in vivo evaluation of the potential effects of simvastatin on cestode larvae.
Fil: Monteiro Guedes, Marina. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Camargo de Lima, Jeferson. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Andrade Paes, Jéssica. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Cevasco Contreras, María del Pilar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Celentano Stanic, Ana Maria Luisa Micaela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Zaha, Arnaldo. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Monteiro, Karina Mariante. Universidade Federal do Rio Grande do Sul; Brasil
Fil: Rosenzvit, Mara Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Bunselmeyer Ferreira, Henrique. Universidade Federal do Rio Grande do Sul; Brasil
description Cestodiases, like echinococcoses and cysticercoses, represent a global health problem. Currently available anthelmintics, as benzimidazoles and praziquantel, have limited effectiveness against these cestodiases, creating a demand for the identification of new and more effective drugs. Here, the potential of statins (simvastatin and fluvastatin), for repositioning as novel anthelmintic is explored. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a main enzyme in the mevalonate pathway, which is vital for the synthesis of non-steroidal isoprenoids and the maintenance of normal cell functioning. A survey for HMG-CoA reductase encoding genes showed that they are present in a single copy in the genomes of parasitic helminths and their mammal hosts. Sequence alignments and phylogenetic analyses showed 20?95% overall identities among ortholog HMG-CoA reductases, with special conservation of their catalytic domains. The HMG-CoA reductase 3D-structure was predicted for orthologs from 3 cestodes of medical importance (Echinococcus multilocularis, Echinococcus granulosus sensu lato, and Taenia solium), and from a model cestode species (Mesocestoides corti). Molecular docking between cestode HMG-CoA reductase orthologs with simvastatin demonstrated that the Arg, Ser, Lys, and Glu residues in conserved positions of the active site interact with this drug, similarly to the interactions predicted for the human reference ortholog enzyme. Furthermore, in vitro assays demonstrated that simvastatin produced a significant reduction of M. corti viability, being able to reduce 100% of parasite viability at 150 μm. Fluvastatin was also assessed showing a lower, although significant anthelmintic effect. The predicted overall structures and interactions together with in vitro assays suggest that cestodes HMG-CoA reductases are inhibited by simvastatin, being a potential therapeutic target for the repurposing of simvastatin as anthelmintic drug. Furthermore, these results pave the way for the in vivo evaluation of the potential effects of simvastatin on cestode larvae.
publishDate 2024
dc.date.none.fl_str_mv 2024-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/266247
Monteiro Guedes, Marina; Camargo de Lima, Jeferson; Andrade Paes, Jéssica; Cevasco Contreras, María del Pilar; Celentano Stanic, Ana Maria Luisa Micaela; et al.; Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model; Cambridge University Press; Parasitology; 13; 12-2024; 1-11
0031-1820
CONICET Digital
CONICET
url http://hdl.handle.net/11336/266247
identifier_str_mv Monteiro Guedes, Marina; Camargo de Lima, Jeferson; Andrade Paes, Jéssica; Cevasco Contreras, María del Pilar; Celentano Stanic, Ana Maria Luisa Micaela; et al.; Repurposing statins for the treatment of larval cestodiases: in silico evaluation of statin-HMG-CoA reductase interactions and assessment of statin effects on a cestode model; Cambridge University Press; Parasitology; 13; 12-2024; 1-11
0031-1820
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.cambridge.org/core/product/identifier/S0031182024001586/type/journal_article
info:eu-repo/semantics/altIdentifier/doi/10.1017/S0031182024001586
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cambridge University Press
publisher.none.fl_str_mv Cambridge University Press
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1844613359083716608
score 13.070432

Publicaciones similares