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dc.creatorSalvador, Guilherme Henrique Marchi
dc.creatorBorges, Rafael J.
dc.creatorLomonte, Bruno
dc.creatorLewin, Matthew R.
dc.creatorFontes, Marcos Roberto de Mattos
dc.date.accessioned2021-05-11T14:19:46Z
dc.date.available2021-05-11T14:19:46Z
dc.date.issued2021
dc.identifier.citationhttps://www.sciencedirect.com/science/article/abs/pii/S0304416521000714?via%3Dihub
dc.identifier.issn0304-4165
dc.identifier.urihttps://hdl.handle.net/10669/83375
dc.description.abstractThe treatment for snakebites is early administration of antivenom, which can be highly effective in inhibiting the systemic effects of snake venoms, but is less effective in the treatment of extra-circulatory and local effects. To complement standard-of-care treatments such as antibody-based antivenoms, natural and synthetic small molecules have been proposed for the inhibition of key venom components such as phospholipase A2 (PLA2) and PLA2-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLA2s. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA2 and PLA2-like toxins. In vivo and in vitro techniques were used to evaluate the inhibitory effect of varespladib against MjTX-I. X-ray crystallography was used to reveal details of the interaction between these molecules. A new methodology that combines crystallography, mass spectroscopy and phylogenetic data was used to review its primary sequence. Varespladib was able to inhibit the myotoxic and cytotoxic effects of MjTX-I. Structural analysis revealed a particular inhibitory mechanism of MjTX-I when compared to other PLA2-like myotoxin, presenting an oligomeric-independent function. Results suggest the effectiveness of varespladib for the inhibition of MjTX-I, in similarity with other PLA2 and PLA2-like toxins. Varespladib appears to be a promissory molecule in the treatment of local effects led by PLA2 and PLA2-like toxins (oligomeric dependent and independent), indicating that this is a multifunctional or broadly specific inhibitor for different toxins within this superfamily.es_ES
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo/[2015/17286-0]/FAPESP/Brasiles_ES
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo/[2016/24191-8]/FAPESP/Brasiles_ES
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico/[302883/2017-7]/CNPq/Brasiles_ES
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior/[]/CAPES/Brasiles_ES
dc.description.sponsorshipUniversidad de Costa Rica/[]/UCR/Costa Ricaes_ES
dc.language.isoenges_ES
dc.sourceBiochimica et Biophysica Acta, vol.1865(7), pp.1-11es_ES
dc.subjectPhospholipase A2 - like proteinses_ES
dc.subjectLys49-phospholipases A2 proteinses_ES
dc.subjectSnake venomes_ES
dc.subjectMyotoxicity inhibitiones_ES
dc.subjectVarespladib inhibitores_ES
dc.subjectPhospholipase A2 inhibitores_ES
dc.titleThe synthetic Varespladib molecule is a multi-functional inhibitor for PLA2 and PLA2-like ophidic toxinses_ES
dc.typeartículo científico
dc.identifier.doi10.1016/j.bbagen.2021.129913
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)es_ES


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