Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors

Detalhes bibliográficos
Autor(a) principal: Lima, Caroline Sprengel [UNESP]
Data de Publicação: 2021
Outros Autores: Mottin, Melina, de Assis, Leticia Ribeiro [UNESP], Mesquita, Nathalya Cristina de Moraes Roso, Sousa, Bruna Katiele de Paula, Coimbra, Lais Durco, Santos, Karina Bispo-dos-, Zorn, Kimberley M., Guido, Rafael V.C., Ekins, Sean, Marques, Rafael Elias, Proença-Modena, José Luiz, Oliva, Glaucius, Andrade, Carolina Horta, Regasini, Luis Octavio [UNESP]
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UNESP
Texto Completo: http://dx.doi.org/10.1016/j.bioorg.2021.104719
http://hdl.handle.net/11449/205925
Resumo: Although the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC50 of 5 μM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.
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spelling Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitorsAntiviralDrug discoveryEmerging arbovirusesEnzyme inhibitorsFlavonoidNS3 proteinProteasePterogyne nitensVirtual screeningZika virusAlthough the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC50 of 5 μM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de GoiásNational Institute of General Medical SciencesLaboratory of Antibiotics and Chemotherapeutics (LAQ) Institute of Biosciences Humanities and Exact Sciences São Paulo State University (Unesp)Laboratory of Molecular Modeling and Drug Design (LabMol) Faculdade de Farmácia Universidade Federal de GoiásInstitute of Physics of São Carlos University of São PauloBrazilian Biosciences National Laboratory (LNBio) Brazilian Center for Research in Energy and Materials (CNPEM)Laboratory of Emerging Viruses (LEVE) Department of Genetics Evolution Microbiology and Immunology Institute of Biology University of Campinas (UNICAMP)Collaborations Pharmaceuticals Inc.Laboratory of Antibiotics and Chemotherapeutics (LAQ) Institute of Biosciences Humanities and Exact Sciences São Paulo State University (Unesp)CAPES: 130767/2016-01CNPq: 150759/2017-7FAPESP: 2013/07600-3FAPESP: 2014/18330-0FAPESP: 2016/00194-8Fundação de Amparo à Pesquisa do Estado de Goiás: 20171026700006FAPESP: 2018/03917-6FAPESP: 2018/15083-2Fundação de Amparo à Pesquisa do Estado de Goiás: 300508/2017-4CNPq: 306251/2016-7CNPq: 309957/2019-2CNPq: 429322/2018-6CNPq: 471129/2013-5National Institute of General Medical Sciences: R43AT010585-01S1Universidade Estadual Paulista (Unesp)Universidade Federal de Goiás (UFG)Universidade de São Paulo (USP)Brazilian Center for Research in Energy and Materials (CNPEM)Universidade Estadual de Campinas (UNICAMP)Inc.Lima, Caroline Sprengel [UNESP]Mottin, Melinade Assis, Leticia Ribeiro [UNESP]Mesquita, Nathalya Cristina de Moraes RosoSousa, Bruna Katiele de PaulaCoimbra, Lais DurcoSantos, Karina Bispo-dos-Zorn, Kimberley M.Guido, Rafael V.C.Ekins, SeanMarques, Rafael EliasProença-Modena, José LuizOliva, GlauciusAndrade, Carolina HortaRegasini, Luis Octavio [UNESP]2021-06-25T10:23:35Z2021-06-25T10:23:35Z2021-04-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.bioorg.2021.104719Bioorganic Chemistry, v. 109.1090-21200045-2068http://hdl.handle.net/11449/20592510.1016/j.bioorg.2021.1047192-s2.0-85101244114Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBioorganic Chemistryinfo:eu-repo/semantics/openAccess2021-10-22T20:04:03Zoai:repositorio.unesp.br:11449/205925Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T15:28:39.584516Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false
dc.title.none.fl_str_mv Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
title Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
spellingShingle Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
Lima, Caroline Sprengel [UNESP]
Antiviral
Drug discovery
Emerging arboviruses
Enzyme inhibitors
Flavonoid
NS3 protein
Protease
Pterogyne nitens
Virtual screening
Zika virus
title_short Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
title_full Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
title_fullStr Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
title_full_unstemmed Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
title_sort Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
author Lima, Caroline Sprengel [UNESP]
author_facet Lima, Caroline Sprengel [UNESP]
Mottin, Melina
de Assis, Leticia Ribeiro [UNESP]
Mesquita, Nathalya Cristina de Moraes Roso
Sousa, Bruna Katiele de Paula
Coimbra, Lais Durco
Santos, Karina Bispo-dos-
Zorn, Kimberley M.
Guido, Rafael V.C.
Ekins, Sean
Marques, Rafael Elias
Proença-Modena, José Luiz
Oliva, Glaucius
Andrade, Carolina Horta
Regasini, Luis Octavio [UNESP]
author_role author
author2 Mottin, Melina
de Assis, Leticia Ribeiro [UNESP]
Mesquita, Nathalya Cristina de Moraes Roso
Sousa, Bruna Katiele de Paula
Coimbra, Lais Durco
Santos, Karina Bispo-dos-
Zorn, Kimberley M.
Guido, Rafael V.C.
Ekins, Sean
Marques, Rafael Elias
Proença-Modena, José Luiz
Oliva, Glaucius
Andrade, Carolina Horta
Regasini, Luis Octavio [UNESP]
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Universidade Estadual Paulista (Unesp)
Universidade Federal de Goiás (UFG)
Universidade de São Paulo (USP)
Brazilian Center for Research in Energy and Materials (CNPEM)
Universidade Estadual de Campinas (UNICAMP)
Inc.
dc.contributor.author.fl_str_mv Lima, Caroline Sprengel [UNESP]
Mottin, Melina
de Assis, Leticia Ribeiro [UNESP]
Mesquita, Nathalya Cristina de Moraes Roso
Sousa, Bruna Katiele de Paula
Coimbra, Lais Durco
Santos, Karina Bispo-dos-
Zorn, Kimberley M.
Guido, Rafael V.C.
Ekins, Sean
Marques, Rafael Elias
Proença-Modena, José Luiz
Oliva, Glaucius
Andrade, Carolina Horta
Regasini, Luis Octavio [UNESP]
dc.subject.por.fl_str_mv Antiviral
Drug discovery
Emerging arboviruses
Enzyme inhibitors
Flavonoid
NS3 protein
Protease
Pterogyne nitens
Virtual screening
Zika virus
topic Antiviral
Drug discovery
Emerging arboviruses
Enzyme inhibitors
Flavonoid
NS3 protein
Protease
Pterogyne nitens
Virtual screening
Zika virus
description Although the widespread epidemic of Zika virus (ZIKV) and its neurological complications are well-known there are still no approved drugs available to treat this arboviral disease or vaccine to prevent the infection. Flavonoids from Pterogyne nitens have already demonstrated anti-flavivirus activity, although their target is unknown. In this study, we virtually screened an in-house database of 150 natural and semi-synthetic compounds against ZIKV NS2B-NS3 protease (NS2B-NS3p) using docking-based virtual screening, as part of the OpenZika project. As a result, we prioritized three flavonoids from P. nitens, quercetin, rutin and pedalitin, for experimental evaluation. We also used machine learning models, built with Assay Central® software, for predicting the activity and toxicity of these flavonoids. Biophysical and enzymatic assays generally agreed with the in silico predictions, confirming that the flavonoids inhibited ZIKV protease. The most promising hit, pedalitin, inhibited ZIKV NS2B-NS3p with an IC50 of 5 μM. In cell-based assays, pedalitin displayed significant activity at 250 and 500 µM, with slight toxicity in Vero cells. The results presented here demonstrate the potential of pedalitin as a candidate for hit-to-lead (H2L) optimization studies towards the discovery of antiviral drug candidates to treat ZIKV infections.
publishDate 2021
dc.date.none.fl_str_mv 2021-06-25T10:23:35Z
2021-06-25T10:23:35Z
2021-04-01
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv http://dx.doi.org/10.1016/j.bioorg.2021.104719
Bioorganic Chemistry, v. 109.
1090-2120
0045-2068
http://hdl.handle.net/11449/205925
10.1016/j.bioorg.2021.104719
2-s2.0-85101244114
url http://dx.doi.org/10.1016/j.bioorg.2021.104719
http://hdl.handle.net/11449/205925
identifier_str_mv Bioorganic Chemistry, v. 109.
1090-2120
0045-2068
10.1016/j.bioorg.2021.104719
2-s2.0-85101244114
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv Bioorganic Chemistry
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.source.none.fl_str_mv Scopus
reponame:Repositório Institucional da UNESP
instname:Universidade Estadual Paulista (UNESP)
instacron:UNESP
instname_str Universidade Estadual Paulista (UNESP)
instacron_str UNESP
institution UNESP
reponame_str Repositório Institucional da UNESP
collection Repositório Institucional da UNESP
repository.name.fl_str_mv Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)
repository.mail.fl_str_mv
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