Abstract
Snake venom metalloproteinases (SVMPs) are predominant in viperid venoms, which provoke hemorrhage and affect hemostasis and thrombosis. P-I class enzymes consist only of a single metalloproteinase domain. Despite sharing high sequence homology, only some of them induce hemorrhage. They have direct fibrin(ogen)olytic activity. Their main biological substrate is fibrin(ogen), whose Aα-chain is degraded rapidly and independently of activation of plasminogen. It is important to understand their biochemical and physiological mechanisms, as well as their applications, to study the etiology of some human diseases and to identify sites of potential intervention. As compared to all current antiplatelet therapies to treat cardiovascular events, the SVMPs have outstanding biochemical attributes: (a) they are insensitive to plasma serine proteinase inhibitors; (b) they have the potential to avoid bleeding risk; (c) mechanistically, they are inactivated/cleared by α2-macroglobulin that limits their range of action in circulation; and (d) few of them also impair platelet aggregation that represent an important target for therapeutic intervention. This review will briefly highlight the structure–function relationships of these few direct-acting fibrinolytic agents, including, barnettlysin-I, isolated from Bothrops barnetti venom, that could be considered as potential agent to treat major thrombotic disorders. Some of their pharmacological advantages are compared with plasmin.
Highlights
Snakes are the best-studied creatures throughout human history; this is partially due to the bad reputation associated with snakes, as many people have experienced that these small and often fragile-looking animals are harmful to man, and can inflict devastating damage in envenomed victims [1]
Snake venoms, especially those of the Viperidae family, contain extremely complex mixtures of pharmacologically active proteins/peptides that disrupt normal physiological or biochemical processes in line with their function to immobilize, to kill, and to digest their prey, as well as to defend themselves from predators [2,3]. They belong to a few structural classes of major protein families, including proteins with and without enzymatic activity, such as metalloproteinases (SVMPs), serine proteinases (SVSPs), phospholipases A2 (PLA2 s), L-amino acid oxidases (L-AAOs), hyaluronidases, and non-enzymatic proteins: disintegrins, C-type lectin-like proteins/snaclecs, bradykinin-potentiating peptides (BPPs), Toxins 2017, 9, 392; doi:10.3390/toxins9120392
P-I SVMP should be mainly limited to fibrin
Summary
Snakes are the best-studied creatures throughout human history; this is partially due to the bad reputation associated with snakes, as many people have experienced that these small and often fragile-looking animals are harmful to man, and can inflict devastating damage in envenomed victims [1]. Snake venoms, especially those of the Viperidae (pit vipers and true vipers) family, contain extremely complex mixtures of pharmacologically active proteins/peptides that disrupt normal physiological or biochemical processes in line with their function to immobilize, to kill, and to digest their prey, as well as to defend themselves from predators [2,3] They belong to a few structural classes of major protein families, including proteins with and without enzymatic activity, such as metalloproteinases (SVMPs), serine proteinases (SVSPs), phospholipases A2 (PLA2 s), L-amino acid oxidases (L-AAOs), hyaluronidases, and non-enzymatic proteins: disintegrins, C-type lectin-like proteins/snaclecs, bradykinin-potentiating peptides (BPPs), Toxins 2017, 9, 392; doi:10.3390/toxins9120392 www.mdpi.com/journal/toxins. Their potential application in therapy of major arterial occlusive disorders is surveyed
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