Natural Inhibitors of Snake Venom Metalloendopeptidases: History and Current Challenges

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.

Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

“…Plants and fungi remain the basis for most active pharmaceutical ingredients used in modern medicine today [ 11 ]. The spectrum of small molecule inhibitor compounds for the treatment of snakebite has been reviewed by Carvalho, Soares, Laustsen, Bastos, and others [ 7 , 12 – 16 ]. As a field, only a small number of individuals and groups have directly addressed the question of developing small molecules for the treatment of snakebite and it remains largely unexplored [ 8 , 17 – 20 ].…”

“…This makes it an inviting candidate for repurposing because of the known safety profile and, thus, potentially reduced development costs [ 8 , 75 , 76 ]. Similarly, MP inhibitors that have previously been developed for cancer treatment such as batimastat, marimastat, and prinomostat could also be considered [ 11 , 12 , 77 , 78 ].…”

<p>Effects of Snake-Derived Phospholipase A2 Inhibitors on Acute Pancreatitis: In vitro and in vivo Characterization</p>

“…8 At present, 21 kinds of PLI are identified in snake serum based on the ExPASY protein database. 9 PLI can also be divided into three categories: PLIα, PLI-β, and PLI-γ. PLI-α and PLI-β exist in Viperidae, and they mainly inhibit the activity of sPLA2; PLI-γ exists in Ophiuchidae, cobra family, and python family, and the range of PLA2 inhibition is wide, including snake sPLA2, mammal PLA 2IIB and IIA, bee venom PLA2.…”

Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

“…Plants and fungi remain the basis for most active pharmaceutical ingredients used in modern medicine today [7]. The spectrum of small molecule inhibitor compounds for the treatment of snakebite has been reviewed by Carvalho, Soares, Lohse, Laustsen, Bastos and others [5,[8][9][10][11]. As a field, only a small number of individuals and groups have directly addressed the question of developing small molecules for the treatment of snakebite and it remains largely unexplored [6,[12][13][14][15].…”