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
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/232623
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/232623
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling 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 Técnicas2025-09-29T10:22:48Zoai: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:34982025-09-29 10:22:49.033CONICET 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
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info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
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dc.identifier.none.fl_str_mv 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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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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