A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity
- Autores
- Turani, Ornella; Castro, Maria Julia; Faraoni, María Belén; Gerbino, Darío César; Bouzat, Cecilia Beatriz
- Año de publicación
- 2020
- Idioma
- inglés
- Tipo de recurso
- documento de conferencia
- Estado
- versión publicada
- Descripción
- Nematode parasitosis causes mortality and morbidity in humans and losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the nematode Caenorhabditis elegans has emerged as a valuable platform. We have previously synthetized a library of compounds and determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping on C. elegans. To identify the drug targets, we performed a screening of strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the glutamate-gated chloride channels (GluCl), which are targets of the antiparasitic ivermectin, is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action.
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
Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica
Argentina
Sociedad Argentina de Biofísica - Materia
-
ANTHELMINTIC ACTIVITY
CHLORIDE CHANNELS - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
.jpg)
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/161169
Ver los metadatos del registro completo
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A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activityTurani, OrnellaCastro, Maria JuliaFaraoni, María BelénGerbino, Darío CésarBouzat, Cecilia BeatrizANTHELMINTIC ACTIVITYCHLORIDE CHANNELShttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Nematode parasitosis causes mortality and morbidity in humans and losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the nematode Caenorhabditis elegans has emerged as a valuable platform. We have previously synthetized a library of compounds and determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping on C. elegans. To identify the drug targets, we performed a screening of strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the glutamate-gated chloride channels (GluCl), which are targets of the antiparasitic ivermectin, is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action.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; ArgentinaPrimeras Jornadas Virtuales de la Sociedad Argentina de BiofísicaArgentinaSociedad Argentina de BiofísicaSociedad Argentina de BiofísicaDelfino, Jose Maria2020info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/conferenceObjectJornadaBookhttp://purl.org/coar/resource_type/c_5794info:ar-repo/semantics/documentoDeConferenciaapplication/pdfapplication/vnd.openxmlformats-officedocument.wordprocessingml.documentapplication/pdfhttp://hdl.handle.net/11336/161169A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 50-50978-987-27591-8-6CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://biofisica.org.ar/reuniones-cientificas/reunionsab-previas/Nacionalinfo:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T09:44:23Zoai:ri.conicet.gov.ar:11336/161169instacron: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 09:44:23.83CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
| dc.title.none.fl_str_mv |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| title |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| spellingShingle |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity Turani, Ornella ANTHELMINTIC ACTIVITY CHLORIDE CHANNELS |
| title_short |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| title_full |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| title_fullStr |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| title_full_unstemmed |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity |
| title_sort |
A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with 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.contributor.none.fl_str_mv |
Delfino, Jose Maria |
| dc.subject.none.fl_str_mv |
ANTHELMINTIC ACTIVITY CHLORIDE CHANNELS |
| topic |
ANTHELMINTIC ACTIVITY CHLORIDE CHANNELS |
| purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
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Nematode parasitosis causes mortality and morbidity in humans and losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the nematode Caenorhabditis elegans has emerged as a valuable platform. We have previously synthetized a library of compounds and determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping on C. elegans. To identify the drug targets, we performed a screening of strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the glutamate-gated chloride channels (GluCl), which are targets of the antiparasitic ivermectin, is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action. 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 Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica Argentina Sociedad Argentina de Biofísica |
| description |
Nematode parasitosis causes mortality and morbidity in humans and losses in livestock and domestic animals. The acquisition of resistance to current anthelmintic drugs has prompted the search for new compounds for which the nematode Caenorhabditis elegans has emerged as a valuable platform. We have previously synthetized a library of compounds and determined that dibenzo[b,e]oxepin-11(6H)-one (doxepinone) reduces swimming rate, induces paralysis, and decreases the rate of pharyngeal pumping on C. elegans. To identify the drug targets, we performed a screening of strains carrying mutations in Cys-loop receptors involved in worm locomotion for determining resistance to doxepinone effects. A mutant strain that lacks subunit genes of the glutamate-gated chloride channels (GluCl), which are targets of the antiparasitic ivermectin, is resistant to doxepinone effects. To unravel the molecular mechanism, we measured whole-cell currents from GluClα1/β receptors expressed in mammalian cells. Glutamate elicits macroscopic currents whereas no responses are elicited by doxepinone, indicating that it is not an agonist of GluCls. Preincubation of the cell with doxepinone produces a significant decrease of the decay time constant and net charge of glutamate-elicited currents, indicating that it inhibits GluCls. Thus, we identify doxepinone as an attractive scaffold with promising anthelmintic activity and propose the inhibition of GluCls as a potential anthelmintic mechanism of action. |
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2020 |
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2020 |
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http://hdl.handle.net/11336/161169 A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 50-50 978-987-27591-8-6 CONICET Digital CONICET |
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A new antagonist of Caenorhabditis elegans glutamate-activated chloride channels with anthelmintic activity; Primeras Jornadas Virtuales de la Sociedad Argentina de Biofísica; Argentina; 2020; 50-50 978-987-27591-8-6 CONICET Digital CONICET |
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eng |
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Sociedad Argentina de Biofísica |
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