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Multifunctional Toxins in Snake Venoms and Therapeutic Implications: From Pain to Hemorrhage and Necrosis

Fernanda C. Cardoso

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- A number of PLA2s exert strong myotoxic effects which often lead to severe necrosis, and many of these toxins promote inflammation, including edema formation, cytokine production and leukocyte recruitment, pain by inducing thermal allodynia and mechanical hyperalgesia, paralysis through block of neuromuscular transmission and intensify hemorrhage by inhibiting coagulation (Table 1).
- Class P-III snake venom metalloproteinases (SVMP) tend to display stronger hemorrhagic activity compared to P-I and P-II SVMPs, possibly due to the disintegrin-like and cysteine-rich domains enabling binding to relevant targets in the extracellular matrix of capillary vessels. The functions of these domains have been investigated in inflammation, revealing that these domains are sufficient to induce pro-inflammatory responses through production of TNF-α, IL-1β and IL-6, and leukocyte migration, in which mechanisms and primary targets are still unknown. These observations suggest that these domains are involved in the inflammatory hyperalgesia induced by SVMPs.
- The multifunctional approach adopted by the major components of their venoms, by using multidomain proteins and peptides with promiscuous folds, as well as their diversity of toxic effects, are unique and yet to be identified in other animal venoms at such level of complexity.
- We hope to improve the therapies used to neutralize the toxic effects of PLA2s, SVMPs, snake venom serine proteases (SVSP) and 3FTXs, and to develop drugs as new antidotes for a broad-spectrum of snake venoms that could be effective in preventing the described inflammatory reactions and pain induced by snakebite.
- A diversity of biological functions in snake venoms is yet to be explored, including their inflammatory properties and their intriguing interactions with sensory neurons and other compartments of the nervous system, which will certainly lead to the elucidation of new biological functions and the development of useful research tools, diagnostics and therapeutics.

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