Snake venoms are a mixture of hydrolases which produce complex pathogenesis such as bleeding, dermo/ myonecrosis, inflammation and coagulation disorders. The toxicity of venoms cannot be attributed to only one component. It is well known that venom components present antagonist activities, while some of them work synergistically. Binding to their intra-and extra-cellular or molecular targets, leads these components to generate severe disturbances which might concern several systems through complex mechanisms. Some of these mechanisms are still not yet elucidated. Thus, some of these components can act at different steps of blood coagulation by activating or inhibiting several molecular or cellular targets thereby inducing blood disorders. Despite their effects, it is well established that some of components from snake venoms present beneficial effects when acting alone as purified entity. Appropriate treatments of snakebite victims need a complete understanding of the pharmacological roles of the different venom components. Thus, this review emphasizes the toxicological relevance of snake venoms mainly those of Viperidae and their components as pharmacological bioactive tools.
Snake venoms contain various molecules that can be used as tools in the diagnosis and in the treatment of hemostatic disorders. This study reports the isolation and functional characterization of a new thrombin-like enzyme and its role in the modulation of platelet aggregation and coagulation. The molecule was purified by gel filtration, anion exchange chromatography and reverse-phase-HPLC on C8 column; its molecular weight was determined. Natural and synthetic substrates were used to evaluate its enzymatic activities. The fibrinogenolytic activity was tested electrophoretically and by reverse-phase-HPLC on C18 column. Otherwise, the effect on blood coagulation and deficient plasma factors were also evaluated. The mechanism by which a thrombin-like enzyme VLCV (thrombin-like enzyme)-induced platelet aggregation was explored in presence of ticlopidin, clopidogrel and aspirin. VLCV (45 kDa) isolated from Vipera lebetina as a thrombin-like enzyme seems to be able to modulate platelet function. This enzyme showed an amidolytic activity by hydrolyzing the chromogenic-specific substrate of thrombin and the α-chain of fibrinogen. It is also able to clot human plasma and the deficient human plasma in factor X, suggesting that it is involved in the intrinsic and common pathways. The aggregating effect of VLCV is more sensitive to ticlopidine than to the clopidogrel suggesting the involvement of ADP/P2Y12/PI3K pathway. VLCV seems to be able to promote human platelet aggregation suggesting an interaction between P2Y12 and PAR1. Due to its ability to replace the missing factor X and its proaggregating activity, VLCV could be used as molecular tool to better understand the hemostasis mechanism.
The current study reported a structure-based molecular docking of Cc2-PLA2, a phospholipase A2 purified from Cerastes cerastes venom by three chromatographic steps. Its molecular weight was equal to 13,534.16 Da and its sequence identified by proteomic analysis consists of 120 amino acid residues. Structurally, when modeled by homology, Cc2-PLA2 3D structure appeared organized into 2 β-strands (11%), 3 α-helices (42%) and 11% disordered structure. To explore their inhibitory effect against Cc2-PLA2 enzymatic activity, curcumin and its analogs, derived from chemical modification of curcumin, were submitted to a molecular docking study. Our results show that all of the curcumin, tetrahydrocurcumin and dihydrocurcumin interact with Cc2-PLA2 by a hydrogen bond established with His 47 . Moreover, hexahydrocurcumin targeted the residue Asp 48 of Cc2-PLA2. Besides this, among all compounds, the most potent complexes were established with hexahydrocurcumin and tetrahdrocurcumin as they show the most negative energies of interaction. This result shows that chemical modification of curcumin promoted its affinity to Cc2-PLA2 and therefore, potentiates the inhibitory effect. His 47 and Asp 48 being involved in the catalytic loop of Cc2-PLA2 thus reinforce the obtained results and confirm the inhibitory effect of the studied compounds against the catalytic activity of our enzyme on its specific substrates. The current study opens perspectives for the design of new snake venom-phospholipase A2 inhibitors and the improvement of envenomation therapy.
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