Repurposing Cancer Drugs Batimastat and Marimastat to Inhibit the Activity of a Group I Metalloprotease from the Venom of the Western Diamondback Rattlesnake, Crotalus atrox
| Autor: | Karthik Lakshminarayanan, Harry F. Williams, Harry J. Layfield, Divyashree Ravishankar, Rajendran Vaiyapuri, Anika Salim, Steven A Trim, Thomas M. Vallance, Sakthivel Vaiyapuri, Amita Mehmi, Andrew B. Bicknell, Ketan Patel, Medha Sonavane |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
rattlesnake
Erythrocytes metalloprotease Protein Conformation Health Toxicology and Mutagenesis Antivenom lcsh:Medicine Venom Matrix metalloproteinase Pharmacology Toxicology Hydroxamic Acids marimastat Substrate Specificity Catalytic Domain snake venom 0303 health sciences Crotalus atrox biology Chemistry Antivenins Fibrinolysis 030302 biochemistry & molecular biology batimastat Molecular Docking Simulation neglected tropical disease Snake venom Collagen Batimastat Marimastat medicine.drug Protein Binding Blood Platelets Phenylalanine Antineoplastic Agents Thiophenes Matrix Metalloproteinase Inhibitors Hemolysis Article 03 medical and health sciences Structure-Activity Relationship Crotalid Venoms medicine Animals Humans Envenomation 030304 developmental biology Fibrin Binding Sites antivenom Crotalus lcsh:R Drug Repositioning biology.organism_classification Matrix Metalloproteinases |
| Zdroj: | Toxins, Vol 12, Iss 309, p 309 (2020) Toxins Volume 12 Issue 5 |
| ISSN: | 2072-6651 |
| Popis: | 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 &mu M, 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|