Structural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladib

dc.contributor.authorSalvador, Guilherme H.M. [UNESP]
dc.contributor.authorPinto, Êmylle K.R.
dc.contributor.authorOrtolani, Paula L.
dc.contributor.authorFortes-Dias, Consuelo L.
dc.contributor.authorCavalcante, Walter L.G.
dc.contributor.authorSoares, Andreimar M.
dc.contributor.authorLomonte, Bruno
dc.contributor.authorLewin, Matthew R.
dc.contributor.authorFontes, Marcos R.M. [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionUniversidade Federal de Minas Gerais (UFMG)
dc.contributor.institutionFundação Ezequiel Dias (FUNED)
dc.contributor.institutionINCT EPIAMO
dc.contributor.institutionUniversidad de Costa Rica
dc.contributor.institutionInc. Corte Madera
dc.contributor.institutionCalifornia Academy of Sciences
dc.description.abstractVarespladib (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.en
dc.description.affiliationDepartamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista, SP
dc.description.affiliationDepartmento de Farmacologia Instituto de Ciências Biologicas Universidade Federal de Minas Gerais (UFMG)
dc.description.affiliationCentro de Pesquisa e Desenvolvimento Fundação Ezequiel Dias (FUNED)
dc.description.affiliationLaboratório 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, RO
dc.description.affiliationInstituto Clodomiro Picado Facultad de Microbiología Universidad de Costa Rica
dc.description.affiliationOphirex Inc. Corte Madera
dc.description.affiliationCenter for Exploration and Travel Health California Academy of Sciences
dc.description.affiliationUnespDepartamento de Biofísica e Farmacologia Instituto de Biociências Universidade Estadual Paulista, SP
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipUniversidad de Costa Rica
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG)
dc.description.sponsorshipIdCNPq: 150448/2022-8
dc.description.sponsorshipIdFAPESP: 2019/05958-4
dc.description.sponsorshipIdFAPESP: 2020/10143-7
dc.description.sponsorshipIdCNPq: 302643/2021-4
dc.description.sponsorshipIdFAPEMIG: APQ-00722-22
dc.identifier.citationBiochimie, v. 207, p. 1-10.
dc.titleStructural basis of the myotoxic inhibition of the Bothrops pirajai PrTX-I by the synthetic varespladiben