The synthetic varespladib molecule is a multi-functional inhibitor for PLA(2) and PLA(2)-like ophidic toxins

Autor(es)

Salvador, Guilherme H. M. ^[1] ; Borges, Rafael J. ^[1] ; Lomonte, Bruno ^[2] ; Lewin, Matthew R. ^[3] ; Fontes, Marcos R. M. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Estadual Paulista UNESP, Inst Biociencias, Dept Biofis & Farmacol, Botucatu, SP - Brazil

^[2] Univ Costa Rica, Fac Microbiol, Inst Clodomiro Picado, San Jose - Costa Rica

^[3] Calif Acad Sci, Ctr Explorat & Travel Hlth, San Francisco, CA 94118 - USA

• Tipo de documento: Artigo Científico
• Fonte: BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS; v. 1865, n. 7 JUL 2021.
• Citações Web of Science: 3

Resumo

Background: The 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 A(2) (PLA(2)) and PLA(2)-like toxins. Varespladib (compound LY315920) is a synthetic molecule developed and clinically tested aiming to block inflammatory cascades of several diseases associated with high PLA(2)s. Recent studies have demonstrated this molecule is able to potently inhibit snake venom catalytic PLA(2) and PLA(2)-like toxins. Methods: 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. Results: 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 PLA(2)-like myotoxin, presenting an oligomeric-independent function. Conclusion: Results suggest the effectiveness of varespladib for the inhibition of MjTX-I, in similarity with other PLA(2) and PLA(2)-like toxins. General significance: Varespladib appears to be a promissory molecule in the treatment of local effects led by PLA(2) and PLA(2)-like toxins (oligomeric dependent and independent), indicating that this is a multifunctional or broadly specific inhibitor for different toxins within this superfamily. (AU)

• Processo FAPESP: 15/17286-0 - Estudos estruturais e funcionais objetivando compreender o papel de toxinas de venenos de serpentes e de como inibir a sua atividade biológica
• Beneficiário: Marcos Roberto de Mattos Fontes
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 16/24191-8 - Desenvolvimento de métodos para elucidação de estruturas cristalográficas e estudos estruturais do mecanismo tóxico de fosfolipases A2 homólogas de veneno de serpente
• Beneficiário: Rafael Junqueira Borges
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado