A novel synthetic quinolinone inhibitor presents proteolytic and hemorrhagic inhibitory activities against snake venom metalloproteases

dc.contributor.authorBaraldi, Patrícia T.
dc.contributor.authorMagro, Angelo J. [UNESP]
dc.contributor.authorMatioli, Fábio F. [UNESP]
dc.contributor.authorMarcussi, Silvana
dc.contributor.authorLemke, Ney [UNESP]
dc.contributor.authorCalderon, Leonardo A.
dc.contributor.authorStábeli, Rodrigo G.
dc.contributor.authorSoares, Andreimar M.
dc.contributor.authorCorrea, Arlene G.
dc.contributor.authorFontes, Marcos R.M. [UNESP]
dc.contributor.institutionUniversidade Federal de São Carlos (UFSCar)
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.contributor.institutionUniversidade Federal de Lavras (UFLA)
dc.contributor.institutionUnidade Fiocruz Rondônia
dc.contributor.institutionUniversidade Federal de Rondônia (UNIR)
dc.date.accessioned2018-12-11T16:59:45Z
dc.date.available2018-12-11T16:59:45Z
dc.date.issued2016-02-01
dc.description.abstractMetalloproteases play a fundamental role in snake venom envenomation inducing hemorrhagic, fibrigen(ogen)olytic and myotoxic effects in their victims. Several snake venoms, such as those from the Bothrops genus, present important local effects which are not efficiently neutralized by conventional serum therapy. Consequently, these accidents may result in permanent sequelae and disability, creating economic and social problems, especially in developing countries, leading the attention of the World Health Organization that considered ophidic envenomations a neglected tropical disease. Aiming to produce an efficient inhibitor against bothropic venoms, we synthesized different molecules classified as quinolinones - a group of low-toxic chemical compounds widely used as antibacterial and antimycobacterial drugs - and tested their inhibitory properties against hemorrhage caused by bothropic venoms. The results from this initial screening indicated the molecule 2-hydroxymethyl-6-methoxy-1,4-dihydro-4-quinolinone (Q8) was the most effective antihemorrhagic compound among all of the assayed synthetic quinolinones. Other in vitro and in vivo experiments showed this novel compound was able to inhibit significantly the hemorrhagic and/or proteolytic activities of bothropic crude venoms and isolated snake venom metalloproteases (SVMPs) even at lower concentrations. Docking and molecular dynamic simulations were also performed to get insights into the structural basis of Q8 inhibitory mechanism against proteolytic and hemorrhagic SVMPs. These structural studies demonstrated that Q8 may form a stable complex with SVMPs, impairing the access of substrates to the active sites of these toxins. Therefore, both experimental and structural data indicate that Q8 compound is an interesting candidate for antiophidic therapy, particularly for the treatment of the hemorrhagic and necrotic effects induced by bothropic venoms.en
dc.description.affiliationDepartamento de Química Universidade Federal de São Carlos (UFSCar)
dc.description.affiliationDepartamento de Bioprocessos e Biotecnologia Faculdade de Ciências Agrárias Universidade Estadual Paulista (UNESP) Campus de Botucatu Fazenda Experimental Lageado, Rua José Barbosa de Barros, 1780
dc.description.affiliationInstituto de Biotecnologia Universidade Estadual Paulista (UNESP)
dc.description.affiliationDepartamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP) Campus de Botucatu, Distrito de Rubirao Júnior, S/N
dc.description.affiliationDepartamento de Química Universidade Federal de Lavras (UFLA)
dc.description.affiliationCentro de Estudos de Biomoléculas Aplicadas À Saúde (CEBio) Fundação Oswaldo Cruz (FIOCRUZ) Unidade Fiocruz Rondônia
dc.description.affiliationDepartamento de Medicina Universidade Federal de Rondônia (UNIR)
dc.description.affiliationUnespDepartamento de Bioprocessos e Biotecnologia Faculdade de Ciências Agrárias Universidade Estadual Paulista (UNESP) Campus de Botucatu Fazenda Experimental Lageado, Rua José Barbosa de Barros, 1780
dc.description.affiliationUnespInstituto de Biotecnologia Universidade Estadual Paulista (UNESP)
dc.description.affiliationUnespDepartamento de Física e Biofísica Instituto de Biociências Universidade Estadual Paulista (UNESP) Campus de Botucatu, Distrito de Rubirao Júnior, S/N
dc.format.extent179-188
dc.identifierhttp://dx.doi.org/10.1016/j.biochi.2015.11.031
dc.identifier.citationBiochimie, v. 121, p. 179-188.
dc.identifier.doi10.1016/j.biochi.2015.11.031
dc.identifier.issn6183-1638
dc.identifier.issn0300-9084
dc.identifier.lattes7977035910952141
dc.identifier.scopus2-s2.0-84950983591
dc.identifier.urihttp://hdl.handle.net/11449/172330
dc.language.isoeng
dc.relation.ispartofBiochimie
dc.relation.ispartofsjr1,554
dc.rights.accessRightsAcesso restrito
dc.sourceScopus
dc.subjectAntihemorrhagic effects
dc.subjectAntiophidic drugs
dc.subjectBioinformatics studies
dc.subjectMetalloproteases
dc.subjectQuinolinones
dc.subjectSnake venom
dc.titleA novel synthetic quinolinone inhibitor presents proteolytic and hemorrhagic inhibitory activities against snake venom metalloproteasesen
dc.typeArtigo
unesp.author.lattes0059017255172730[2]
unesp.author.lattes7977035910952141
unesp.author.orcid0000-0002-4253-6992[2]

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