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Toxins (Basel) ; 12(5)2020 05 09.
Article in English | MEDLINE | ID: mdl-32397419

ABSTRACT

Snakebite envenomation causes over 140,000 deaths every year, predominantly in developing countries. As a result, it is one of the most lethal neglected tropical diseases. It is associated with incredibly complex pathophysiology due to the vast number of unique toxins/proteins present in the venoms of diverse snake species found worldwide. Here, we report the purification and functional characteristics of a Group I (PI) metalloprotease (CAMP-2) from the venom of the western diamondback rattlesnake, Crotalus atrox. Its sensitivity to matrix metalloprotease inhibitors (batimastat and marimastat) was established using specific in vitro experiments and in silico molecular docking analysis. CAMP-2 shows high sequence homology to atroxase from the venom of Crotalus atrox and exhibits collagenolytic, fibrinogenolytic and mild haemolytic activities. It exerts a mild inhibitory effect on agonist-induced platelet aggregation in the absence of plasma proteins. Its collagenolytic activity is completely inhibited by batimastat and marimastat. Zinc chloride also inhibits the collagenolytic activity of CAMP-2 by around 75% at 50 µM, while it is partially potentiated by calcium chloride. Molecular docking studies have demonstrated that batimastat and marimastat are able to bind strongly to the active site residues of CAMP-2. This study demonstrates the impact of matrix metalloprotease inhibitors in the modulation of a purified, Group I metalloprotease activities in comparison to the whole venom. By improving our understanding of snake venom metalloproteases and their sensitivity to small molecule inhibitors, we can begin to develop novel and improved treatment strategies for snakebites.


Subject(s)
Antineoplastic Agents/pharmacology , Antivenins/pharmacology , Crotalid Venoms/antagonists & inhibitors , Crotalus/metabolism , Drug Repositioning , Hydroxamic Acids/pharmacology , Matrix Metalloproteinase Inhibitors/pharmacology , Matrix Metalloproteinases/metabolism , Phenylalanine/analogs & derivatives , Thiophenes/pharmacology , Animals , Antineoplastic Agents/chemistry , Antivenins/chemistry , Binding Sites , Blood Platelets/drug effects , Blood Platelets/metabolism , Catalytic Domain , Collagen/metabolism , Crotalid Venoms/enzymology , Erythrocytes/drug effects , Erythrocytes/metabolism , Fibrin/metabolism , Fibrinolysis/drug effects , Hemolysis/drug effects , Humans , Hydroxamic Acids/chemistry , Matrix Metalloproteinase Inhibitors/chemistry , Matrix Metalloproteinases/chemistry , Molecular Docking Simulation , Phenylalanine/chemistry , Phenylalanine/pharmacology , Protein Binding , Protein Conformation , Structure-Activity Relationship , Substrate Specificity , Thiophenes/chemistry
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