A synthetic human sPLA2 inhibitor varespladib was found to possess the ability to neutralize a variety of snake venoms worldwide, with significant prolongation of survival time on rats that were inoculated with varespladib simultaneously or following exposure . 2,500,000 are envenomed, 125,000 die, and more than 100,000 individuals suffer from severe sequelae each year . Unfortunately, snakebite was neglected by governments and international health agencies for a long time, even though the snake bite mortality rate is equivalent to one-fifth of the deaths from malaria worldwide and half of the deaths from HIV/AIDS in India . In 2009 2009 the World Health Organization (WHO) recognized snake bite as a neglected tropical disease . Currently, antivenin is the only specific treatment towards envenomation. Although the immunized animal sera (mainly horse or sheep) presently used are highly effective, they are limited by a few drawbacks . First, local tissue damage resulting from snake venom exposure, often leading to amputation, cannot be reversed by antivenin . Furthermore, early and late adverse reactions to antivenin (e.g., anaphylaxis, pyrogenic reactions, and serum sickness) occur in some cases . Additionally, access to antivenins is usually often limited. Some remote, rural communities where antivenoms are most needed cannot get adequate supplies, due to the lack of cold chain storage and other complex political reasons. Finally, most antivenoms are too expensive for the patient’s family in low-income countries . Recently, the nonprofit French drug firm Sanofi Pasteur had ceased the production of Fav-Afrique, the most effective antivenin against Africa’s vipers, mambas, and cobras. This has resulted in a large-scale snakebite crisis in rural Africa . This alarming situation demonstrates the need for antivenin replacements and new antivenom drug candidates. This review article focuses on snake venom phospholipase A2s (svPLA2s), a chemical family that is widely distributed in venomous snake species. Here we describe svPLA2s, the antienvenomation effects of their inhibitors, and the potential of being a common target for broad-spectrum antivenom drugs. 2. Characteristics of svPLA2 Snake venoms are complicated mixtures, consisting of phospholipase A2s, metalloproteases, C-lectins, serine proteases, L-amino acid oxidases, disintegrins, and a few other compounds . Most svPLA2s hydrolyze glycerophospholipids at the sn-2 position of the glycerol backbone, freeing lysophospholipids, and fatty acids. svPLA2s share 44C99% amino acid identity in their primarily structure, which results to high similarity in their tertiary structure . Based on their size, location, function, substrate specificity, and calcium requirement, PLA2s are classified into six families. svPLA2 belongs to the secretory PLA2 (sPLA2) family (groups IA, IIA, and IIB) [9C11]. Cobras and kraits, rattlesnakes, and Gaboon vipers have svPLA2s in groups IA, IIA, and IIB, respectively . There are also group IB enzymes which are mainly found in mammalian pancreas that have RTA-408 been reported in some snake venoms, such asOxyuranus scutellatus,Pseudonaja textilis, andMicrurus frontalis frontalis. These compounds are conserved in structure and have comparable molecular masses (~10C20?kDa), 5C7 disulfide bonds, and analogous three-dimensional structures . In Group I there are approximately 115C120 residues, 7 disulfide bonds (the unique disulfide linking residues 11 and 77), and G IA has a characteristic surface loop between residues 63 to 67 called elapidic loop . While G RTA-408 IB has a five amino acids residues (residues 62C67) extension termed pancreatic loop, some G IB snake venom PLA2 even has an eight-residue propeptide segment in their mature state [13, 16]. In contrast, Group II has a C-terminal extension, the unique disulfide linking residues 50 and 137. GIIA have a 7-residue C-terminal extension and seven conserved disulfide bonds, while in Group IIB, the C-terminal extension is usually KDM6A 6 residues, and only six disulfides remained in which a universally conserved 61C95 disulfide is usually lacking RTA-408 . Furthermore, a new subgroup (Lys49 PLA2 homologues) can be created through mutation. Replacement of the 49th residue (asparagine) with lysine results within an inactive or weakly poisonous PLA2. This lysine.