Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib
Autor(a) principal: | |
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Data de Publicação: | 2023 |
Outros Autores: | , , , , , , , |
Tipo de documento: | Artigo |
Idioma: | eng |
Título da fonte: | Repositório Institucional da UNESP |
Texto Completo: | http://dx.doi.org/10.1016/j.biochi.2022.11.006 http://hdl.handle.net/11449/246364 |
Resumo: | Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A2 (PLA2) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA2. Recently, varespladib was also found to inhibit snake venom PLA2 and PLA2-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA2-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA2-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA2-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA2 and PLA2-like toxins. |
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Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladibVarespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A2 (PLA2) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA2. Recently, varespladib was also found to inhibit snake venom PLA2 and PLA2-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA2-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA2-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA2-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA2 and PLA2-like toxins.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)Universidad de Costa RicaConselho 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 Minas Gerais (FAPEMIG)Departamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista, SPDepartmento de Farmacologia Instituto de Ciências Biologicas Universidade Federal de Minas Gerais (UFMG)Centro de Pesquisa e Desenvolvimento Fundação Ezequiel Dias (FUNED)Laboratório de Biotecnologia de Proteínas e Compostos Bioativos Aplicados à Saúde LABIOPROT Fundação Oswaldo Cruz FIOCRUZ unidade Rondônia e Instituto Nacional de Ciência e Tecnologia de Epidemiologia da Amazônia Ocidental INCT EPIAMO, ROInstituto Clodomiro Picado Facultad de Microbiología Universidad de Costa RicaOphirex Inc. Corte MaderaCenter for Exploration and Travel Health California Academy of SciencesDepartamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista, SPCNPq: 150448/2022-8FAPESP: 2019/05958-4FAPESP: 2020/10143-7CNPq: 302643/2021-4FAPEMIG: APQ-00722-22Universidade Estadual Paulista (UNESP)Universidade Federal de Minas Gerais (UFMG)Fundação Ezequiel Dias (FUNED)INCT EPIAMOUniversidad de Costa RicaInc. Corte MaderaCalifornia Academy of SciencesSalvador, Guilherme H.M. [UNESP]Pinto, Êmylle K.R.Ortolani, Paula L.Fortes-Dias, Consuelo L.Cavalcante, Walter L.G.Soares, Andreimar M.Lomonte, BrunoLewin, Matthew R.Fontes, Marcos R.M. [UNESP]2023-07-29T12:38:59Z2023-07-29T12:38:59Z2023-04-01info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article1-10http://dx.doi.org/10.1016/j.biochi.2022.11.006Biochimie, v. 207, p. 1-10.6183-16380300-9084http://hdl.handle.net/11449/24636410.1016/j.biochi.2022.11.0062-s2.0-85142513976Scopusreponame:Repositório Institucional da UNESPinstname:Universidade Estadual Paulista (UNESP)instacron:UNESPengBiochimieinfo:eu-repo/semantics/openAccess2023-07-29T12:38:59Zoai:repositorio.unesp.br:11449/246364Repositório InstitucionalPUBhttp://repositorio.unesp.br/oai/requestopendoar:29462024-08-05T21:02:53.753822Repositório Institucional da UNESP - Universidade Estadual Paulista (UNESP)false |
dc.title.none.fl_str_mv |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
title |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
spellingShingle |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib Salvador, Guilherme H.M. [UNESP] |
title_short |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
title_full |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
title_fullStr |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
title_full_unstemmed |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
title_sort |
Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib |
author |
Salvador, Guilherme H.M. [UNESP] |
author_facet |
Salvador, Guilherme H.M. [UNESP] Pinto, Êmylle K.R. Ortolani, Paula L. Fortes-Dias, Consuelo L. Cavalcante, Walter L.G. Soares, Andreimar M. Lomonte, Bruno Lewin, Matthew R. Fontes, Marcos R.M. [UNESP] |
author_role |
author |
author2 |
Pinto, Êmylle K.R. Ortolani, Paula L. Fortes-Dias, Consuelo L. Cavalcante, Walter L.G. Soares, Andreimar M. Lomonte, Bruno Lewin, Matthew R. Fontes, Marcos R.M. [UNESP] |
author2_role |
author author author author author author author author |
dc.contributor.none.fl_str_mv |
Universidade Estadual Paulista (UNESP) Universidade Federal de Minas Gerais (UFMG) Fundação Ezequiel Dias (FUNED) INCT EPIAMO Universidad de Costa Rica Inc. Corte Madera California Academy of Sciences |
dc.contributor.author.fl_str_mv |
Salvador, Guilherme H.M. [UNESP] Pinto, Êmylle K.R. Ortolani, Paula L. Fortes-Dias, Consuelo L. Cavalcante, Walter L.G. Soares, Andreimar M. Lomonte, Bruno Lewin, Matthew R. Fontes, Marcos R.M. [UNESP] |
description |
Varespladib (LY315920) is a potent inhibitor of human group IIA phospholipase A2 (PLA2) originally developed to control inflammatory cascades of diseases associated with high or dysregulated levels of endogenous PLA2. Recently, varespladib was also found to inhibit snake venom PLA2 and PLA2-like toxins. Herein, ex vivo neuromuscular blocking activity assays were used to test the inhibitory activity of varespladib. The binding affinity between varespladib and a PLA2-like toxin was quantified and compared with other potential inhibitors for this class of proteins. Crystallographic and bioinformatic studies showed that varespladib binds to PrTX-I and BthTX-I into their hydrophobic channels, similarly to other previously characterized PLA2-like myotoxins. However, a new finding is that an additional varespladib binds to the MDiS region, a particular site that is related to muscle cell disruption by these toxins. The present results further advance the characterization of the molecular interactions of varespladib with PLA2-like myotoxins and provide additional evidence for this compound as a promising inhibitor candidate for different PLA2 and PLA2-like toxins. |
publishDate |
2023 |
dc.date.none.fl_str_mv |
2023-07-29T12:38:59Z 2023-07-29T12:38:59Z 2023-04-01 |
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.biochi.2022.11.006 Biochimie, v. 207, p. 1-10. 6183-1638 0300-9084 http://hdl.handle.net/11449/246364 10.1016/j.biochi.2022.11.006 2-s2.0-85142513976 |
url |
http://dx.doi.org/10.1016/j.biochi.2022.11.006 http://hdl.handle.net/11449/246364 |
identifier_str_mv |
Biochimie, v. 207, p. 1-10. 6183-1638 0300-9084 10.1016/j.biochi.2022.11.006 2-s2.0-85142513976 |
dc.language.iso.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
Biochimie |
dc.rights.driver.fl_str_mv |
info:eu-repo/semantics/openAccess |
eu_rights_str_mv |
openAccess |
dc.format.none.fl_str_mv |
1-10 |
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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1808129277491675136 |