Novel Apigenin Based Small Molecule that Targets Snake Venom Metalloproteases

Abstract

The classical antivenom therapy has appreciably reduced snakebite mortality rate and thus is the only savior drug available. Unfortunately, it considerably fails to shield the viper bite complications like hemorrhage, local tissue degradation and necrosis responsible for severe morbidity. Moreover, the therapy is also tagged with limitations including anaphylaxis, serum sickness and poor availability. Over the last decade, snake venom metalloproteases (SVMPs) are reported to be the primary component responsible for hemorrhage and tissue degradation at bitten site. Thus, antivenom inability to offset viper venom-induced local toxicity has been a basis for an insistent search for SVMP inhibitors. Here we report the inhibitory effect of compound 5d, an apigenin based molecule against SVMPs both in silico and in vivo. Several apigenin analogues are synthesized using multicomponent Ugi reactions. Among them, compound 5d effectively abrogated Echis carinatus (EC) venom-induced local hemorrhage, tissue necrosis and myotoxicity in a dose dependant fashion. The histopathological study further conferred effective inhibition of basement membrane degradation, and accumulation of inflammatory leucocytes at the site of EC venom inoculation. The compound also protected EC venom-induced fibrin and fibrinogen degradation. The molecular docking of compound 5d and bothropasin demonstrated the direct interaction of hydroxyl group of compound with Glu146 present in hydrophobic pocket of active site and does not chelate Zn2+. Hence, it is concluded that compound 5d could be a potent agent in viper bite management.

Inhibitory Effects of Hydroethanolic Leaf Extracts of Kalanchoe brasiliensis and Kalanchoe pinnata (Crassulaceae) against Local Effects Induced by Bothrops jararaca Snake Venom

“…According to the literature, the presence of flavonoids could be especially interesting in antiophidic plants since these compounds are able to promote strong hydrogen bonds with amides of protein chains and exhibit metal chelating activity, as well as present potent anti-inflammatory and antioxidant activities [28, 36]. In fact, several studies show that flavonoids (such as apigenin, moreloflavone, quercetin, luteolin, among others) have the ability to inhibit SVMPs, PLA 2 s, and hyaluronidases purified from snake venoms, showing great inhibitory effects against envenoming-induced local effects [60, 61, 62, 63, 64, 65]. So, the great amounts of flavonoids in raw materials and extracts of K .…”

Inhibition of a Snake Venom Metalloproteinase by the Flavonoid Myricetin

“…Later, diverse studies demonstrated the ability of these compounds to inhibit MMP-1 [ 32 ], MMP-2 and MMP-9 [ 33 ], among others. Similary, gallocatechin and apigenin derivatives have been shown to antagonize the hemorrhagic activity of venoms and purified toxins from different Viperidae venoms [ 17 , 34 ]. Nonetheless, thus far, the most active recognized SVMP inhibitor is the peptidomimetic Batimastat, a compound that inhibits BaP1 proteolytic activity on biotinylated casein, with an IC value of 80 nM.…”

Qualitative/Chemical Analyses of Ankaferd Hemostat and Its Antioxidant Content in Synthetic Gastric Fluids

“…Apigenin has been detected in the molecular library of ABS in this present study. Apigenin has inhibitory effects against the snake venom metalloproteases, the main component accountable for the hemorrhage and tissue degradation at the bitten site [ 59 ]. Therefore, the already established antihemorrhagic efficacy of ABS and its apigenin content shall be searched in future toxicological experiments.…”