Viperbites undeniably cause local manifestations such as
hemorrhage and
myotoxicity involving substantial degradation of extracellular matrix (ECM) at the site of envenomation and lead to progressive tissue damage and
necrosis. The principle toxin responsible is attributed to
snake venom metalloproteases (SVMPs). Treatment of such progressive tissue damage induced by SVMPs has become a challenging task for researchers and medical practitioners who are in quest of SVMPs inhibitors. In this study, we have evaluated the inhibitory potential of three specific
zinc (Zn(2+))
chelating agents; N,N,N',N'-tetrakis (2-pyridylmethyl)
ethane-1,2-diamine (
TPEN),
diethylene triamine pentaacetic
acid (
DTPA), tetraethyl
thiuram disulfide (TTD) on Echis carinatus
venom (ECV) induced
hemorrhage and
myotoxicity. Amongst them,
TPEN has high affinity for Zn(2+) and revealed potent inhibition of ECV
metalloproteases (ECVMPs) in vitro (IC50: 6.7 μM) compared to
DTPA and TTD. The specificity of
TPEN towards Zn(2+) was confirmed by spectral and docking studies. Further,
TPEN,
DTPA, and TTD completely blocked the hemorrhagic and myotoxic activities of ECV in a dose dependent manner upon co-injection; whereas, only
TPEN successfully neutralized
hemorrhage and
myotoxicity following independent injection. Histological examinations revealed that
TPEN effectively prevents degradation of dermis and basement membrane surrounding the blood vessels in mouse skin sections.
TPEN also prevents muscle
necrosis and accumulation of inflammatory cells at the site of ECV
injections. In conclusion, a high degree of structural and functional homology between mammalian
MMPs and SVMPs suggests that specific Zn(2+)
chelators currently in clinical practice could be potent
first aid therapeutic agents in
snakebite management, particularly for local tissue damage.