Neutralization of the haemorrhagic activities of viperine snake venoms and venom metalloproteinases using synthetic peptide inhibitors and chelators.
Envenoming by the West African saw-scaled viper, Echis ocellatus resembles that of most vipers, in that it results in local blistering, necrosis and sometimes life-threatening systemic haemorrhage. While effective against systemic envenoming, current antivenoms have little or no effect against local tissue damage. The major mediators of local venom pathology are the zinc-dependant snake venom metalloproteinases (SVMPs). The high degree of structural and functional homology between SVMPs and their mammalian relatives the matrix metalloproteinases (MMPs) suggests that substrate/inhibitor interactions between these subfamilies are likely to be analogous. In this study, four recently developed MMP inhibitors (MMPIs) (Marimastat, AG-3340, CGS-270 23A and Bay-12 9566) are evaluated in addition to three metal ion chelators (EDTA, TPEN and BAPTA) for their ability to inhibit the haemorrhagic activities of the medically important E. ocellatus venom and one of its haemorrhagic SVMPs, EoVMP2. As expected, the metal ion chelators significantly inhibited the haemorrhagic activities of both whole E. ocellatus venom and EoVMP2, while the synthetic MMPIs show more variation in their efficacies. These variations suggest that individual MMPIs show specificity towards SVMPs and that their application to the neutralization of local haemorrhage may require a synthetic MMPI mixture, ensuring that a close structural component for each SVMP is represented.
Howes
J-M
JM
Alistair Reid Venom Research Unit, Liverpool School of Tropical Medicine, Pembroke Place, Liverpool L3 5QA, UK.
Theakston
R D G
RD
Laing
G D
GD
D000818:Animals; D001713:Biphenyl Compounds; D002614:Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002850:Chromatography, Gel; D002853:Chromatography, Liquid; D004492:Edetic Acid / Q000494:pharmacology / Q000627:therapeutic use; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005029:Ethylenediamines / Q000494:pharmacology / Q000627:therapeutic use; D005069:Evaluation Studies as Topic; D006470:Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D045726:Metalloproteases / Q000037:antagonists & inhibitors* / Q000633:toxicity; D051379:Mice; D015394:Molecular Structure; D009930:Organic Chemicals / Q000494:pharmacology / Q000627:therapeutic use; D010654:Phenylbutyrates; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D012909:Snake Bites / Q000150:complications / Q000188:drug therapy*; D018709:Statistics, Nonparametric; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014757:Viper Venoms / Q000037:antagonists & inhibitors* / Q000633:toxicity
D001713:Biphenyl Compounds; C097658:CGS 27023A; D002614:Chelating Agents; D005029:Ethylenediamines; D006877:Hydroxamic Acids; D009930:Organic Chemicals; D010654:Phenylbutyrates; D047428:Protein Kinase Inhibitors; D011719:Pyrazines; D013449:Sulfonamides; D014757:Viper Venoms; C113282:prinomastat; D004533:Egtazic Acid; D004492:Edetic Acid; C113281:Bay 12-9566; C100342:marimastat; D045726:Metalloproteases; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine