Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability
- Autores
- Schoijet, Alejandra Cecilia; Prego, Alejo Facundo; Vilchez Larrea, Salomé Catalina; Llanos, Manuel; Alberca, Lucas Nicolás; Bellera, Carolina Leticia; Gavernet, Luciana; Talevi, Alan; Alonso, Guillermo Daniel
- Año de publicación
- 2022
- Idioma
- inglés
- Tipo de recurso
- documento de conferencia
- Estado
- versión publicada
- Descripción
- The intracellular cAMP and cGMP levels are regulated by cyclic nucleotide phosphodiesterases (PDEs), a group of specific cyclic nucleotide-degrading enzymes involved in the control of homeostasis. It is long been self-evident that increased knowledge of cyclic nucleotide signaling pathways can lead to the development of therapeutic agents against human diseases. The kinetoplastid PDEs are highly similar to most of the human homologs, which justifies the potential repurposing of PDE inhibitors as potential antiparasitic agents. Also, these PDEs are highly amenable to selective inhibition, due to small differences in their binding pockets. Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug treatment and discovery. Among other methods, cell-based washout experiments, in which the phenotypic consequences of target engagement are evaluated once drug is “removed” from the system, can provide direct insight into target vulnerability. In this work, washout experiments were performed to test the effect of three commercial PDE inhibitors: Rolipram, Zaprinast and Vinpocetine. Post-washout infection inhibition was maintained for all inhibitors, but Vinpocetine showed the largest detrimental effect on in vitro T. cruzi infection experiments. This inhibitor also proved to be effective in trypomastigotes and amastigotes. As additional experiments in order to support target validation, we tested two other compounds from in silico studies, Terameprocol and Lasalocid. Both compounds showed to be effective at low concentrations in the amastigote stage in our experimental model. Finally, we evaluated the effect of both drugs on enzymatic activity using TcrPDEB2 and TcrPDEC recombinant T. cruzi enzymes. Both compounds showed activity inhibition at low concentrations. In summary, these results highlight the potential of PDEs as targets against Chagas´ disease.
Fil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Prego, Alejo Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
Fil: Llanos, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Gavernet, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina
Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina
XI Congreso de la Sociedad Argentina de Protozoología
Mendoza
Argentina
Sociedad Argentina de Protozoología - Materia
-
PDEs
TRYPANOSOMA CRUZI
PHOSPHODIESTERASE - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/232623
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Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerabilitySchoijet, Alejandra CeciliaPrego, Alejo FacundoVilchez Larrea, Salomé CatalinaLlanos, ManuelAlberca, Lucas NicolásBellera, Carolina LeticiaGavernet, LucianaTalevi, AlanAlonso, Guillermo DanielPDEsTRYPANOSOMA CRUZIPHOSPHODIESTERASEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The intracellular cAMP and cGMP levels are regulated by cyclic nucleotide phosphodiesterases (PDEs), a group of specific cyclic nucleotide-degrading enzymes involved in the control of homeostasis. It is long been self-evident that increased knowledge of cyclic nucleotide signaling pathways can lead to the development of therapeutic agents against human diseases. The kinetoplastid PDEs are highly similar to most of the human homologs, which justifies the potential repurposing of PDE inhibitors as potential antiparasitic agents. Also, these PDEs are highly amenable to selective inhibition, due to small differences in their binding pockets. Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug treatment and discovery. Among other methods, cell-based washout experiments, in which the phenotypic consequences of target engagement are evaluated once drug is “removed” from the system, can provide direct insight into target vulnerability. In this work, washout experiments were performed to test the effect of three commercial PDE inhibitors: Rolipram, Zaprinast and Vinpocetine. Post-washout infection inhibition was maintained for all inhibitors, but Vinpocetine showed the largest detrimental effect on in vitro T. cruzi infection experiments. This inhibitor also proved to be effective in trypomastigotes and amastigotes. As additional experiments in order to support target validation, we tested two other compounds from in silico studies, Terameprocol and Lasalocid. Both compounds showed to be effective at low concentrations in the amastigote stage in our experimental model. Finally, we evaluated the effect of both drugs on enzymatic activity using TcrPDEB2 and TcrPDEC recombinant T. cruzi enzymes. Both compounds showed activity inhibition at low concentrations. In summary, these results highlight the potential of PDEs as targets against Chagas´ disease.Fil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Prego, Alejo Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Llanos, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Gavernet, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; ArgentinaFil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaXI Congreso de la Sociedad Argentina de ProtozoologíaMendozaArgentinaSociedad Argentina de ProtozoologíaUniversidad Nacional de Cuyo. Facultad de Ciencias Médicas2022info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectCongresoJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/232623Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability; XI Congreso de la Sociedad Argentina de Protozoología; Mendoza; Argentina; 2022; 129-1291669-8991CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://bdigital.uncu.edu.ar/objetos_digitales/17095/resumenes-congreso-sap.pdfNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:04:12Zoai:ri.conicet.gov.ar:11336/232623instacron: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:34982025-09-03 10:04:12.698CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
title |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
spellingShingle |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability Schoijet, Alejandra Cecilia PDEs TRYPANOSOMA CRUZI PHOSPHODIESTERASE |
title_short |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
title_full |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
title_fullStr |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
title_full_unstemmed |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
title_sort |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability |
dc.creator.none.fl_str_mv |
Schoijet, Alejandra Cecilia Prego, Alejo Facundo Vilchez Larrea, Salomé Catalina Llanos, Manuel Alberca, Lucas Nicolás Bellera, Carolina Leticia Gavernet, Luciana Talevi, Alan Alonso, Guillermo Daniel |
author |
Schoijet, Alejandra Cecilia |
author_facet |
Schoijet, Alejandra Cecilia Prego, Alejo Facundo Vilchez Larrea, Salomé Catalina Llanos, Manuel Alberca, Lucas Nicolás Bellera, Carolina Leticia Gavernet, Luciana Talevi, Alan Alonso, Guillermo Daniel |
author_role |
author |
author2 |
Prego, Alejo Facundo Vilchez Larrea, Salomé Catalina Llanos, Manuel Alberca, Lucas Nicolás Bellera, Carolina Leticia Gavernet, Luciana Talevi, Alan Alonso, Guillermo Daniel |
author2_role |
author author author author author author author author |
dc.subject.none.fl_str_mv |
PDEs TRYPANOSOMA CRUZI PHOSPHODIESTERASE |
topic |
PDEs TRYPANOSOMA CRUZI PHOSPHODIESTERASE |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The intracellular cAMP and cGMP levels are regulated by cyclic nucleotide phosphodiesterases (PDEs), a group of specific cyclic nucleotide-degrading enzymes involved in the control of homeostasis. It is long been self-evident that increased knowledge of cyclic nucleotide signaling pathways can lead to the development of therapeutic agents against human diseases. The kinetoplastid PDEs are highly similar to most of the human homologs, which justifies the potential repurposing of PDE inhibitors as potential antiparasitic agents. Also, these PDEs are highly amenable to selective inhibition, due to small differences in their binding pockets. Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug treatment and discovery. Among other methods, cell-based washout experiments, in which the phenotypic consequences of target engagement are evaluated once drug is “removed” from the system, can provide direct insight into target vulnerability. In this work, washout experiments were performed to test the effect of three commercial PDE inhibitors: Rolipram, Zaprinast and Vinpocetine. Post-washout infection inhibition was maintained for all inhibitors, but Vinpocetine showed the largest detrimental effect on in vitro T. cruzi infection experiments. This inhibitor also proved to be effective in trypomastigotes and amastigotes. As additional experiments in order to support target validation, we tested two other compounds from in silico studies, Terameprocol and Lasalocid. Both compounds showed to be effective at low concentrations in the amastigote stage in our experimental model. Finally, we evaluated the effect of both drugs on enzymatic activity using TcrPDEB2 and TcrPDEC recombinant T. cruzi enzymes. Both compounds showed activity inhibition at low concentrations. In summary, these results highlight the potential of PDEs as targets against Chagas´ disease. Fil: Schoijet, Alejandra Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Prego, Alejo Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Vilchez Larrea, Salomé Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina Fil: Llanos, Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina Fil: Alberca, Lucas Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina Fil: Bellera, Carolina Leticia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina Fil: Gavernet, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina Fil: Talevi, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencas Exactas. Laboratorio de Investigación y Desarrollo de Bioactivos; Argentina Fil: Alonso, Guillermo Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina XI Congreso de la Sociedad Argentina de Protozoología Mendoza Argentina Sociedad Argentina de Protozoología |
description |
The intracellular cAMP and cGMP levels are regulated by cyclic nucleotide phosphodiesterases (PDEs), a group of specific cyclic nucleotide-degrading enzymes involved in the control of homeostasis. It is long been self-evident that increased knowledge of cyclic nucleotide signaling pathways can lead to the development of therapeutic agents against human diseases. The kinetoplastid PDEs are highly similar to most of the human homologs, which justifies the potential repurposing of PDE inhibitors as potential antiparasitic agents. Also, these PDEs are highly amenable to selective inhibition, due to small differences in their binding pockets. Correlating target engagement with in vivo drug activity remains a central challenge in efforts to improve the efficiency of drug treatment and discovery. Among other methods, cell-based washout experiments, in which the phenotypic consequences of target engagement are evaluated once drug is “removed” from the system, can provide direct insight into target vulnerability. In this work, washout experiments were performed to test the effect of three commercial PDE inhibitors: Rolipram, Zaprinast and Vinpocetine. Post-washout infection inhibition was maintained for all inhibitors, but Vinpocetine showed the largest detrimental effect on in vitro T. cruzi infection experiments. This inhibitor also proved to be effective in trypomastigotes and amastigotes. As additional experiments in order to support target validation, we tested two other compounds from in silico studies, Terameprocol and Lasalocid. Both compounds showed to be effective at low concentrations in the amastigote stage in our experimental model. Finally, we evaluated the effect of both drugs on enzymatic activity using TcrPDEB2 and TcrPDEC recombinant T. cruzi enzymes. Both compounds showed activity inhibition at low concentrations. In summary, these results highlight the potential of PDEs as targets against Chagas´ disease. |
publishDate |
2022 |
dc.date.none.fl_str_mv |
2022 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/conferenceObject Congreso Journal http://purl.org/coar/resource_type/c_5794 info:ar-repo/semantics/documentoDeConferencia |
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http://hdl.handle.net/11336/232623 Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability; XI Congreso de la Sociedad Argentina de Protozoología; Mendoza; Argentina; 2022; 129-129 1669-8991 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/232623 |
identifier_str_mv |
Pharmacological investigation of Trypanosoma cruzi phosphodiesterases as drug targets: Insight into target vulnerability; XI Congreso de la Sociedad Argentina de Protozoología; Mendoza; Argentina; 2022; 129-129 1669-8991 CONICET Digital CONICET |
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eng |
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eng |
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dc.publisher.none.fl_str_mv |
Universidad Nacional de Cuyo. Facultad de Ciencias Médicas |
publisher.none.fl_str_mv |
Universidad Nacional de Cuyo. Facultad de Ciencias Médicas |
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