Abstract
The research on natural snake venom metalloendopeptidase inhibitors (SVMPIs) began in the 18th century with the pioneering work of Fontana on the resistance that vipers exhibited to their own venom. During the past 40 years, SVMPIs have been isolated mainly from the sera of resistant animals, and characterized to different extents. They are acidic oligomeric glycoproteins that remain biologically active over a wide range of pH and temperature values. Based on primary structure determination, mammalian plasmatic SVMPIs are classified as members of the immunoglobulin (Ig) supergene protein family, while the one isolated from muscle belongs to the ficolin/opsonin P35 family. On the other hand, SVMPIs from snake plasma have been placed in the cystatin superfamily. These natural antitoxins constitute the first line of defense against snake venoms, inhibiting the catalytic activities of snake venom metalloendopeptidases through the establishment of high-affinity, non-covalent interactions. This review presents a historical account of the field of natural resistance, summarizing its main discoveries and current challenges, which are mostly related to the limitations that preclude three-dimensional structural determinations of these inhibitors using “gold-standard” methods; perspectives on how to circumvent such limitations are presented. Potential applications of these SVMPIs in medicine are also highlighted.
Highlights
IntroductionSnakes and their venoms have always driven the fascination and curiosity of mankind—including the desire to freely handle them without being harmed by the venomous effects of their bites
Snakes and their venoms have always driven the fascination and curiosity of mankind—including the desire to freely handle them without being harmed by the venomous effects of their bites.Members of some ancient tribes used to drink small amounts of venom seeking protection from future envenomation; curiously, individuals from other tribes were thought to be resistant as a consequence of having snake blood running through their veins [1].The idea that snakes could be resistant to their own venom traces back to Greek philosophers and physicians
These natural inhibitors are distributed in two major classes—the phospholipases A2 inhibitors (PLIs), which effectively inhibit the neuro- and myotoxic effects of snake venoms, and the snake venom metalloendopeptidase inhibitors (SVMPIs), which can suppress the hemorrhagic symptoms commonly associated with Viperidae envenomation
Summary
Snakes and their venoms have always driven the fascination and curiosity of mankind—including the desire to freely handle them without being harmed by the venomous effects of their bites. The second mechanism, on which this review will focus, involves the occurrence of serum proteins that neutralize the toxins by forming noncovalent complexes, rendering them unable to exert their pathophysiological effects [21]. These natural inhibitors are distributed in two major classes—the phospholipases A2 inhibitors (PLIs), which effectively inhibit the neuro- and myotoxic effects of snake venoms (for comprehensive reviews see [22,23,24]), and the SVMPIs, which can suppress the hemorrhagic symptoms commonly associated with Viperidae envenomation.
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