Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors
Autor(a) principal: | |
---|---|
Data de Publicação: | 2021 |
Outros Autores: | , , , , , , , , , , , , , |
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. |
id |
UNSP_50ad5a1888bbd97d9c97c3664004ddba |
---|---|
oai_identifier_str |
oai:repositorio.unesp.br:11449/205925 |
network_acronym_str |
UNSP |
network_name_str |
Repositório Institucional da UNESP |
repository_id_str |
2946 |
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 |
|
_version_ |
1808128517870714880 |