A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity

Autores
Turani, Ornella; Castro, Maria Julia; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Nematode parasitoses cause mortality and morbidity in humans and considerable losses in livestock, domestic animals and food crops. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds. The free-living nematode Caenorhabditis elegans has emerged as a valuable platform for anthelmintic drug discovery. We have previously synthetized a small library of oxygenated tricyclic compounds and tested anthelmintic actions by measuring rapid effects on C. elegans. Exposure to dibenzo[b,e]oxepin-11(6H)-one (C1a) induced paralysis of C. elegans. We here sought to identify its target site and mechanism of action. Given that Cys-loop receptors are involved in worm locomotion and are targets of classical antiparasitic drugs, we tested the effects of C1a on several C. elegans mutant strains lacking these receptors. We found that a mutant strain that lacks the invertebrate glutamate-gated chloride-selective channel (GluClR), which is the target of the widely used antiparasitic ivermectin, is resistant to C1a. Thus, the paralysis assays revealed that GluClR is the main drug target of C1a. To unravel the molecular mechanism underlying the paralyzing action, we expressed in mammalian cells GluClα and β subunits to form GluClRs and evaluated the effects of C1a by electrophysiological whole-cell recordings. Glutamate elicited macroscopic currents from cells expressing GluClα/β heteromeric receptors whereas C1a was not capable of eliciting responses, thus indicating that it is not an agonist of GluClRs and that its mechanism differs from that of ivermectin. We found that C1a acts as an inhibitor of glutamate-responses: Preincubation of the cell with C1a produced a statistically significant decrease of the decay time constant and total charge and a slight decrease of the peak of currents elicited by glutamate. We here propose C1a as a novel compound or scaffold with promising antiparasitic activity mediated through inhibition of GluClRs.
Fil: Turani, Ornella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Reunión Anual de Sociedades de Biociencia
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
Materia
C. ELEGANS
ANTHELMINTIC ACTIVITY
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:11336/154068
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/154068
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activityTurani, OrnellaCastro, Maria JuliaFaraoni, María BelénGerbino, Darío CésarBouzat, Cecilia BeatrizC. ELEGANSANTHELMINTIC ACTIVITYhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nematode parasitoses cause mortality and morbidity in humans and considerable losses in livestock, domestic animals and food crops. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds. The free-living nematode Caenorhabditis elegans has emerged as a valuable platform for anthelmintic drug discovery. We have previously synthetized a small library of oxygenated tricyclic compounds and tested anthelmintic actions by measuring rapid effects on C. elegans. Exposure to dibenzo[b,e]oxepin-11(6H)-one (C1a) induced paralysis of C. elegans. We here sought to identify its target site and mechanism of action. Given that Cys-loop receptors are involved in worm locomotion and are targets of classical antiparasitic drugs, we tested the effects of C1a on several C. elegans mutant strains lacking these receptors. We found that a mutant strain that lacks the invertebrate glutamate-gated chloride-selective channel (GluClR), which is the target of the widely used antiparasitic ivermectin, is resistant to C1a. Thus, the paralysis assays revealed that GluClR is the main drug target of C1a. To unravel the molecular mechanism underlying the paralyzing action, we expressed in mammalian cells GluClα and β subunits to form GluClRs and evaluated the effects of C1a by electrophysiological whole-cell recordings. Glutamate elicited macroscopic currents from cells expressing GluClα/β heteromeric receptors whereas C1a was not capable of eliciting responses, thus indicating that it is not an agonist of GluClRs and that its mechanism differs from that of ivermectin. We found that C1a acts as an inhibitor of glutamate-responses: Preincubation of the cell with C1a produced a statistically significant decrease of the decay time constant and total charge and a slight decrease of the peak of currents elicited by glutamate. We here propose C1a as a novel compound or scaffold with promising antiparasitic activity mediated through inhibition of GluClRs.Fil: Turani, Ornella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaFil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; ArgentinaReunión Anual de Sociedades de BiocienciaMar del PlataArgentinaSociedad Argentina de Investigación ClínicaAsociación Argentina de Farmacología ExperimentalSociedad Argentina de BiologíaSociedad Argentina de ProtozoologíaAsociación Argentina de NanomedicinasAsociación Argentina de Ciencia y Tecnología de Animales de LaboratorioFundación Revista Medicina2019info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectReuniónJournalhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/154068A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity; Reunión Anual de Sociedades de Biociencia ; Mar del Plata; Argentina; 2019; 208-2080025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.saic.org.ar/revista-medicinaNacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:45:06Zoai:ri.conicet.gov.ar:11336/154068instacron: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 10:45:07.05CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
title A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
spellingShingle A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
Turani, Ornella
C. ELEGANS
ANTHELMINTIC ACTIVITY
title_short A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
title_full A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
title_fullStr A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
title_full_unstemmed A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
title_sort A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity
dc.creator.none.fl_str_mv Turani, Ornella
Castro, Maria Julia
Faraoni, María Belén
Gerbino, Darío César
Bouzat, Cecilia Beatriz
author Turani, Ornella
author_facet Turani, Ornella
Castro, Maria Julia
Faraoni, María Belén
Gerbino, Darío César
Bouzat, Cecilia Beatriz
author_role author
author2 Castro, Maria Julia
Faraoni, María Belén
Gerbino, Darío César
Bouzat, Cecilia Beatriz
author2_role author
author
author
author
dc.subject.none.fl_str_mv C. ELEGANS
ANTHELMINTIC ACTIVITY
topic C. ELEGANS
ANTHELMINTIC ACTIVITY
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Nematode parasitoses cause mortality and morbidity in humans and considerable losses in livestock, domestic animals and food crops. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds. The free-living nematode Caenorhabditis elegans has emerged as a valuable platform for anthelmintic drug discovery. We have previously synthetized a small library of oxygenated tricyclic compounds and tested anthelmintic actions by measuring rapid effects on C. elegans. Exposure to dibenzo[b,e]oxepin-11(6H)-one (C1a) induced paralysis of C. elegans. We here sought to identify its target site and mechanism of action. Given that Cys-loop receptors are involved in worm locomotion and are targets of classical antiparasitic drugs, we tested the effects of C1a on several C. elegans mutant strains lacking these receptors. We found that a mutant strain that lacks the invertebrate glutamate-gated chloride-selective channel (GluClR), which is the target of the widely used antiparasitic ivermectin, is resistant to C1a. Thus, the paralysis assays revealed that GluClR is the main drug target of C1a. To unravel the molecular mechanism underlying the paralyzing action, we expressed in mammalian cells GluClα and β subunits to form GluClRs and evaluated the effects of C1a by electrophysiological whole-cell recordings. Glutamate elicited macroscopic currents from cells expressing GluClα/β heteromeric receptors whereas C1a was not capable of eliciting responses, thus indicating that it is not an agonist of GluClRs and that its mechanism differs from that of ivermectin. We found that C1a acts as an inhibitor of glutamate-responses: Preincubation of the cell with C1a produced a statistically significant decrease of the decay time constant and total charge and a slight decrease of the peak of currents elicited by glutamate. We here propose C1a as a novel compound or scaffold with promising antiparasitic activity mediated through inhibition of GluClRs.
Fil: Turani, Ornella. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Castro, Maria Julia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Faraoni, María Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Gerbino, Darío César. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; Argentina
Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Reunión Anual de Sociedades de Biociencia
Mar del Plata
Argentina
Sociedad Argentina de Investigación Clínica
Asociación Argentina de Farmacología Experimental
Sociedad Argentina de Biología
Sociedad Argentina de Protozoología
Asociación Argentina de Nanomedicinas
Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
description Nematode parasitoses cause mortality and morbidity in humans and considerable losses in livestock, domestic animals and food crops. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds. The free-living nematode Caenorhabditis elegans has emerged as a valuable platform for anthelmintic drug discovery. We have previously synthetized a small library of oxygenated tricyclic compounds and tested anthelmintic actions by measuring rapid effects on C. elegans. Exposure to dibenzo[b,e]oxepin-11(6H)-one (C1a) induced paralysis of C. elegans. We here sought to identify its target site and mechanism of action. Given that Cys-loop receptors are involved in worm locomotion and are targets of classical antiparasitic drugs, we tested the effects of C1a on several C. elegans mutant strains lacking these receptors. We found that a mutant strain that lacks the invertebrate glutamate-gated chloride-selective channel (GluClR), which is the target of the widely used antiparasitic ivermectin, is resistant to C1a. Thus, the paralysis assays revealed that GluClR is the main drug target of C1a. To unravel the molecular mechanism underlying the paralyzing action, we expressed in mammalian cells GluClα and β subunits to form GluClRs and evaluated the effects of C1a by electrophysiological whole-cell recordings. Glutamate elicited macroscopic currents from cells expressing GluClα/β heteromeric receptors whereas C1a was not capable of eliciting responses, thus indicating that it is not an agonist of GluClRs and that its mechanism differs from that of ivermectin. We found that C1a acts as an inhibitor of glutamate-responses: Preincubation of the cell with C1a produced a statistically significant decrease of the decay time constant and total charge and a slight decrease of the peak of currents elicited by glutamate. We here propose C1a as a novel compound or scaffold with promising antiparasitic activity mediated through inhibition of GluClRs.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/publishedVersion
info:eu-repo/semantics/conferenceObject
Reunión
Journal
http://purl.org/coar/resource_type/c_5794
info:ar-repo/semantics/documentoDeConferencia
status_str publishedVersion
format conferenceObject
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/154068
A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity; Reunión Anual de Sociedades de Biociencia ; Mar del Plata; Argentina; 2019; 208-208
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/154068
identifier_str_mv A novel inhibitor of C. elegans glutamate-activated chloride channel with potential anthelmintic activity; Reunión Anual de Sociedades de Biociencia ; Mar del Plata; Argentina; 2019; 208-208
0025-7680
1669-9106
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.saic.org.ar/revista-medicina
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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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
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dc.coverage.none.fl_str_mv Nacional
dc.publisher.none.fl_str_mv Fundación Revista Medicina
publisher.none.fl_str_mv Fundación Revista Medicina
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
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