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Study of the proteases and peptides present in the Tityus serrulatus scorpion venom: deepening knowledge on the venom and seeking for new therapies aimed at treating envenomation

Grant number: 19/20832-7
Support type:Regular Research Grants
Duration: December 01, 2019 - November 30, 2021
Field of knowledge:Health Sciences - Collective Health - Public Health
Principal researcher:Fernanda Calheta Vieira Portaro
Grantee:Fernanda Calheta Vieira Portaro
Home Institution: Instituto Butantan. Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Scorpionism has grown alarmingly in Brazil in recent years. The occurrence of accidents is associated with the adaptation and proliferation of scorpions in urban areas, where they find shelter, food, and the absence of natural predators. Along with this, the yellow scorpion (Tityus serrulatus), the species responsible for the greatest number of serious accidents, reproduces by parthenogenesis. T. serrulatus envenomation causes local pain and may lead to systemic manifestations, both severe, and, in serious cases, heart failure and pulmonary edema which can be fatal, especially in children below 14 years of age. Recent "omics" approaches revealed that about 40% of its venom is made up of peptides and more than 30% by proteolytic enzymes. However, little is known about the role of these molecules in scorpionism. Regarding the proteases, our group isolated, for the first time, and characterized biochemically three metallopeptidases of this venom, an ACE-like and metalloserrulases 3 and 4 (TsMS 3 and TsMS 4). Even more relevant, we correlated the proteolytic levels with the venom lethality, indicating that the proteases, although little studied, can be here considered important toxins acting in the envenomation. Thus, one of the objectives of this project is to continue the studies with TsMS 3 and TsMS 4 and to isolate and functionally characterize other peptidases present in the Tityus serrulatus venom. Preliminary results indicate that TsMS 3 and TsMS 4 lack cytotoxicity at the concentrations tested, and can induce increased production of proinflammatory cytokines, IL-6, MCP-1, and TNF-±, in murine macrophages. These results indicate that metalloserrulases may play a role in the inflammatory process present in T. serrulatus envenomation. As a consequence, the possible TACE-like activity of metalloserrulases, especially TsMS 3, requires further investigation. We also need to investigate the possible action of the venom and its isolated peptidases on the HGFA-HGF-Met pathway, which can be triggered in response to tissue injury and inflammation. Regarding the peptides, we have to characterize these molecules for the development of new, efficient drugs. In recent work, we identified and sequenced more than 700 linear peptides present in the venom that indicated an atypical processing profile, since they are fragments of larger molecules already described, mainly neurotoxins. These results need to be finalized, and, to date, 10% of the peptides (70 sequences) have been subjected to three in silico analysis platforms, in order to verify the antimicrobial and antifungal potentials of the sequences. The results are interesting and promising, and we need to finish the in silico analysis. After that, the most promising analogous synthetic peptides for the confirmation of the possible biological activity will be acquired. (AU)

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VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)