Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry

Autores
Fidalgo, Daniela Marina; Battini, Leandro; Alvarez, Diego; Bollini, Mariela
Año de publicación
2019
Idioma
inglés
Tipo de recurso
documento de conferencia
Estado
versión publicada
Descripción
Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family. It is transmitted by mosquitoes of the Aedes species and is characterized by severe polyarthralgia that may last for months. Until today, no antiviral agent or vaccine has been approved for treatment or prevention of CHIKV infection. Virus invasion of the host cells is mediated by the envelope proteins, E1 and E2. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention. Our goal was to design and synthesize lead compounds that can interact with a druggable pocket at the interface of the E1-E2 heterodimer. First, we used Autodock Vina to perform a virtual screening of commercially available compounds from Maybridge and Chembridge libraries. Selected compounds were bought or synthesized, and then tested against CHIKV using a reporter virus assay. Compound CHIK-1 showed a good antiviral activity (EC50 1,0 μM) and a selectivity greater than 50. Time of drug addition assays showed that CHIK-1 exerts its antiviral activity in the early stages of the viral life cycle. As CHIK-1 has a chiral center, we analyzed the antiviral activity of R and S enantiomers. To this end, we performed an enantioselective synthesis using as intermediary enantioenriched epoxides that were prepared using a methodology described in the literature. Based on molecular dynamics simulation (MD), forty-one CHIK-1 derivatives were designed and synthesized. Seven derivatives displayed low micromolar activity using a recombinant CHIKV-GFP reporter assay. Furthermore, pharmacokinetic in vitro and solubility assay for active compounds are currently ongoing. In conclusion, we uncovered novel entry inhibitors against CHIKV by prospective docking-based virtual screening and MD optimization. Now, we are seeking the solubility and stability optimization of lead compounds.
Fil: Fidalgo, Daniela Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Battini, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Alvarez, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Reunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
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
CHIKUNGUNYA VIRUS
ANTIVIRAL
E1-E2 HETERODIMER
VIRTUAL SCREENING
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:11336/273285
Acceder
id CONICETDig_edb98c51bc34bd7a7c9d4081a6e2c86c
oai_identifier_str oai:ri.conicet.gov.ar:11336/273285
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entryFidalgo, Daniela MarinaBattini, LeandroAlvarez, DiegoBollini, MarielaCHIKUNGUNYA VIRUSANTIVIRALE1-E2 HETERODIMERVIRTUAL SCREENINGhttps://purl.org/becyt/ford/1.4https://purl.org/becyt/ford/1Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family. It is transmitted by mosquitoes of the Aedes species and is characterized by severe polyarthralgia that may last for months. Until today, no antiviral agent or vaccine has been approved for treatment or prevention of CHIKV infection. Virus invasion of the host cells is mediated by the envelope proteins, E1 and E2. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention. Our goal was to design and synthesize lead compounds that can interact with a druggable pocket at the interface of the E1-E2 heterodimer. First, we used Autodock Vina to perform a virtual screening of commercially available compounds from Maybridge and Chembridge libraries. Selected compounds were bought or synthesized, and then tested against CHIKV using a reporter virus assay. Compound CHIK-1 showed a good antiviral activity (EC50 1,0 μM) and a selectivity greater than 50. Time of drug addition assays showed that CHIK-1 exerts its antiviral activity in the early stages of the viral life cycle. As CHIK-1 has a chiral center, we analyzed the antiviral activity of R and S enantiomers. To this end, we performed an enantioselective synthesis using as intermediary enantioenriched epoxides that were prepared using a methodology described in the literature. Based on molecular dynamics simulation (MD), forty-one CHIK-1 derivatives were designed and synthesized. Seven derivatives displayed low micromolar activity using a recombinant CHIKV-GFP reporter assay. Furthermore, pharmacokinetic in vitro and solubility assay for active compounds are currently ongoing. In conclusion, we uncovered novel entry inhibitors against CHIKV by prospective docking-based virtual screening and MD optimization. Now, we are seeking the solubility and stability optimization of lead compounds.Fil: Fidalgo, Daniela Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Battini, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Alvarez, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaFil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; ArgentinaReunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de LaboratorioMar 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/pdfhttp://hdl.handle.net/11336/273285Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry; Reunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 225-2250025-76801669-9106CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.medicinabuenosaires.com/PMID/32692316.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 Técnicas2025-10-15T14:36:23Zoai:ri.conicet.gov.ar:11336/273285instacron: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:34982025-10-15 14:36:23.562CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
title Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
spellingShingle Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
Fidalgo, Daniela Marina
CHIKUNGUNYA VIRUS
ANTIVIRAL
E1-E2 HETERODIMER
VIRTUAL SCREENING
title_short Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
title_full Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
title_fullStr Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
title_full_unstemmed Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
title_sort Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry
dc.creator.none.fl_str_mv Fidalgo, Daniela Marina
Battini, Leandro
Alvarez, Diego
Bollini, Mariela
author Fidalgo, Daniela Marina
author_facet Fidalgo, Daniela Marina
Battini, Leandro
Alvarez, Diego
Bollini, Mariela
author_role author
author2 Battini, Leandro
Alvarez, Diego
Bollini, Mariela
author2_role author
author
author
dc.subject.none.fl_str_mv CHIKUNGUNYA VIRUS
ANTIVIRAL
E1-E2 HETERODIMER
VIRTUAL SCREENING
topic CHIKUNGUNYA VIRUS
ANTIVIRAL
E1-E2 HETERODIMER
VIRTUAL SCREENING
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.4
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family. It is transmitted by mosquitoes of the Aedes species and is characterized by severe polyarthralgia that may last for months. Until today, no antiviral agent or vaccine has been approved for treatment or prevention of CHIKV infection. Virus invasion of the host cells is mediated by the envelope proteins, E1 and E2. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention. Our goal was to design and synthesize lead compounds that can interact with a druggable pocket at the interface of the E1-E2 heterodimer. First, we used Autodock Vina to perform a virtual screening of commercially available compounds from Maybridge and Chembridge libraries. Selected compounds were bought or synthesized, and then tested against CHIKV using a reporter virus assay. Compound CHIK-1 showed a good antiviral activity (EC50 1,0 μM) and a selectivity greater than 50. Time of drug addition assays showed that CHIK-1 exerts its antiviral activity in the early stages of the viral life cycle. As CHIK-1 has a chiral center, we analyzed the antiviral activity of R and S enantiomers. To this end, we performed an enantioselective synthesis using as intermediary enantioenriched epoxides that were prepared using a methodology described in the literature. Based on molecular dynamics simulation (MD), forty-one CHIK-1 derivatives were designed and synthesized. Seven derivatives displayed low micromolar activity using a recombinant CHIKV-GFP reporter assay. Furthermore, pharmacokinetic in vitro and solubility assay for active compounds are currently ongoing. In conclusion, we uncovered novel entry inhibitors against CHIKV by prospective docking-based virtual screening and MD optimization. Now, we are seeking the solubility and stability optimization of lead compounds.
Fil: Fidalgo, Daniela Marina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Battini, Leandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Alvarez, Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Fil: Bollini, Mariela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Bionanociencias "Elizabeth Jares Erijman"; Argentina
Reunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio
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 Chikungunya virus (CHIKV) is a member of the Alphavirus genus of the Togaviridae family. It is transmitted by mosquitoes of the Aedes species and is characterized by severe polyarthralgia that may last for months. Until today, no antiviral agent or vaccine has been approved for treatment or prevention of CHIKV infection. Virus invasion of the host cells is mediated by the envelope proteins, E1 and E2. Antiviral targeting of virus envelope proteins is an effective strategy for therapeutic intervention. Our goal was to design and synthesize lead compounds that can interact with a druggable pocket at the interface of the E1-E2 heterodimer. First, we used Autodock Vina to perform a virtual screening of commercially available compounds from Maybridge and Chembridge libraries. Selected compounds were bought or synthesized, and then tested against CHIKV using a reporter virus assay. Compound CHIK-1 showed a good antiviral activity (EC50 1,0 μM) and a selectivity greater than 50. Time of drug addition assays showed that CHIK-1 exerts its antiviral activity in the early stages of the viral life cycle. As CHIK-1 has a chiral center, we analyzed the antiviral activity of R and S enantiomers. To this end, we performed an enantioselective synthesis using as intermediary enantioenriched epoxides that were prepared using a methodology described in the literature. Based on molecular dynamics simulation (MD), forty-one CHIK-1 derivatives were designed and synthesized. Seven derivatives displayed low micromolar activity using a recombinant CHIKV-GFP reporter assay. Furthermore, pharmacokinetic in vitro and solubility assay for active compounds are currently ongoing. In conclusion, we uncovered novel entry inhibitors against CHIKV by prospective docking-based virtual screening and MD optimization. Now, we are seeking the solubility and stability optimization of lead compounds.
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/11336/273285
Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry; Reunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 225-225
0025-7680
1669-9106
CONICET Digital
CONICET
url http://hdl.handle.net/11336/273285
identifier_str_mv Targeting of chikungunya virus envelope protein as an antiviral strategy to inhibit cell entry; Reunión Anual de Sociedades de Biociencia 2019; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica; LI Reunión Anual de la Asociación Argentina de Farmacología Experimental; XXI Reunión Anual de la Sociedad Argentina de Biología; XXXI Reunión Anual de la Sociedad Argentina de Protozoología; IX Reunión Anual de la Asociación Argentina de Nanomedicinas y VI Reunión Científica Regional de la Asociación Argentina de Ciencia y Tecnología de Animales de Laboratorio; Mar del Plata; Argentina; 2019; 225-225
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.medicinabuenosaires.com/PMID/32692316.pdf
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.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
_version_ 1846082829931249664
score 13.22299

Publicaciones similares