Structural basis of phospholipase A2-like myotoxin inhibition by chicoric acid, a novel potent inhibitor of ophidian toxins

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dc.contributor.authorCardoso, Fábio F. [UNESP]
dc.contributor.authorBorges, Rafael J. [UNESP]
dc.contributor.authorDreyer, Thiago R. [UNESP]
dc.contributor.authorSalvador, Guilherme H.M. [UNESP]
dc.contributor.authorCavalcante, Walter L.G. [UNESP]
dc.contributor.authorPai, Maeli Dal [UNESP]
dc.contributor.authorGallacci, Márcia [UNESP]
dc.contributor.authorFontes, Marcos R.M. [UNESP]
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade Federal de Minas Gerais (UFMG)
dc.date.accessioned2018-12-11T17:38:18Z
dc.date.available2018-12-11T17:38:18Z
dc.date.issued2018-12-01
dc.description.abstractBackground: Specific compounds found in vegetal species have been demonstrated to be efficient inhibitors of snake toxins, such as phospholipase A2-like (PLA2-like) proteins. These particular proteins, present in several species of vipers (Viperidae), induce a severe local myotoxic effect in prey and human victims, and this effect is often not efficiently neutralized by the regular serum therapy. PLA2-like proteins have been functionally and structurally studied since the early 1990s; however, a comprehensive molecular mechanism was proposed only recently. Methods: Myographic and histological techniques were used to evaluate the inhibitory effect of chicoric acid (CA) against BthTX-I myotoxin. Isothermal titration calorimetry assays were used to measure the affinity between the inhibitor and the toxin. X-ray crystallography was used to reveal details of this interaction. Results: CA prevented the blockade of indirectly evoked muscle contraction and inhibited muscle damage induced by BthTX-I. The inhibitor binds to the toxin with the highest affinity measured for a natural compound in calorimetric assays. The crystal structure and molecular dynamics simulations demonstrated that CA binds at the entrance of the hydrophobic channel of the toxin and binds to one of the clusters that participates in membrane disruption. Conclusions: CA prevents the myotoxic activity of the toxin, preventing its activation by simultaneous binding with two critical regions. General significance: CA is a potential myotoxic inhibitor to other PLA2-like proteins and a possible candidate to complement serum therapy.en
dc.description.affiliationDepartamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.affiliationDepartamento de Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.affiliationDepartamento de Morfologia Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.affiliationDepartamento de Farmacologia Instituto de Ciências Biológicas Universidade Federal de Minas Gerais (UFMG)
dc.description.affiliationUnespDepartamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.affiliationUnespDepartamento de Farmacologia Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.affiliationUnespDepartamento de Morfologia Instituto de Biociências Universidade Estadual Paulista (UNESP)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
dc.description.sponsorshipIdCAPES: 1592/2011
dc.description.sponsorshipIdFAPESP: 2012/07112-6
dc.description.sponsorshipIdFAPESP: 2015/17286-0
dc.description.sponsorshipIdCNPq: 302883/2017-7
dc.description.sponsorshipIdCNPq: 401190/2017-7
dc.format.extent2728-2737
dc.identifierhttp://dx.doi.org/10.1016/j.bbagen.2018.08.002
dc.identifier.citationBiochimica et Biophysica Acta - General Subjects, v. 1862, n. 12, p. 2728-2737, 2018.
dc.identifier.doi10.1016/j.bbagen.2018.08.002
dc.identifier.issn1872-8006
dc.identifier.issn0304-4165
dc.identifier.lattes6171323341671821
dc.identifier.lattes9353490382598257
dc.identifier.scopus2-s2.0-85052443430
dc.identifier.urihttp://hdl.handle.net/11449/180134
dc.language.isoeng
dc.relation.ispartofBiochimica et Biophysica Acta - General Subjects
dc.relation.ispartofsjr1,671
dc.rights.accessRightsAcesso restrito
dc.sourceScopus
dc.subjectLys49-phospholipases A2 proteins
dc.subjectMyotoxic mechanism
dc.subjectMyotoxicity inhibition
dc.subjectPhospholipase A2-like proteins
dc.subjectPlant compound inhibitor
dc.subjectSnake venom
dc.titleStructural basis of phospholipase A2-like myotoxin inhibition by chicoric acid, a novel potent inhibitor of ophidian toxinsen
dc.typeArtigo
unesp.author.lattes6171323341671821
unesp.author.lattes9353490382598257

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Artigos - Morfologia - IBB
Artigos - Farmacologia - IBB