Current Topics in Medicinal Chemistry, 2007, 7, 000-000 1 1568-0266/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Snake Venom Phospholipase A 2 Inhibitors: Medicinal Chemistry and Therapeutic Potential Silvana Marcussi a,b , Carolina D. Sant’Ana a , Clayton Z. Oliveira a , Aristides Quintero Rueda a,c , Danilo L. Menaldo a , Rene O. Beleboni d , Rodrigo G. Stabeli e , José R. Giglio b , Marcos R. M. Fontes f and Andreimar M. Soares a, * a Departamento de Análises Clínicas, Toxicológicas e Bromatológicas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, FCFRP, Universidade de São Paulo, USP-RP, Ribeirão Preto-SP, Brazil; b Departamento de Bioquímica e Imunologia, Faculdade de Ciências Médicas de Ribeirão Preto, FMRP, Universidade de São Paulo, USP- RP, Ribeirão Preto-SP, Brazil; c Departamento de Química, Faculdade de Ciencias Naturaes e Exactas, Universidade Autónoma de Chiriquí, UNACHI, Chiriquí, Panamá; d Departamento de Biotecnologia, Universidade de Ribeirão Preto, UNAERP-SP, Ribeirão Preto, Brazil; e Instituto de Pesquisas em Patologias Tropical, IPEPATRO, Universidade Federal de Rondônia, UNIR, Rondônia-RO, Brazil; f Departamento de Física e Biofísica, Instituto de Biociências, Universidade Estadual Paulista, UNESP, Botucatu-SP, Brazil. Abstract: Phospholipases A 2 (PLA 2 s) are commonly found in snake venoms from Viperidae, Hydrophidae and Elaphidae families and have been extensively studied due to their pharmacological and physiopathological effects in living organisms. This article reports a review on natural and artificial inhibitors of enzymatic, toxic and pharmacological effects induced by snake venom PLA 2 s. These inhibitors act on PLA 2 s through different mechanisms, most of them still not completely understood, including binding to specific domains, denaturation, modification of specific amino acid residues and others. Several substances have been evaluated regarding their effects against snake venoms and isolated toxins, including plant extracts and compounds from marine animals, mammals and snakes serum plasma, in addition to poly or monoclonal antibodies and several synthetic molecules. Research involving these inhibitors may be useful to understand the mechanism of action of PLA 2 s and their role in envenomations caused by snake bite. Furthermore, the biotechnological potential of PLA 2 inhibitors may provide therapeutic molecular models with antiophidian activity to supplement the conventional serum therapy against these multifunctional enzymes. Keywords: Phospholipases A 2 , phospholipase A 2 inhibitors, natural and artificial inhibitors, snake venoms. 1. INTRODUCTION Global health statistics for incidence of snake bite envenomations and their severity remain unknown or misun- derstood. In spite of the lack of data, a global estimation of the number of ophidian accidents reaches one million cases per year, accounting for 20,000 deaths, especially along rural areas in Asia, South America and Africa. In addition to mortality, these envenomations are also a public health concern as a result of the chronic morbidity associated with them (e.g. amputations, deformations and renal failure), which causes significant social and economic impact [1, 2]. Snake venoms induce shock, proteolysis, blood clotting, release of bioactive substances such as histamine and bradykinin, hemorrhage, necrosis and several other effects [3]. Necrosis may result from a direct action of myotoxins or myotoxic PLA 2 s on muscle cell plasma memb-ranes, or indirectly, as a consequence of blood vessel dege-neration and schemia caused by hemorrhagins. Disorga-nization of membrane phospholipid components promotes release of intracellular creatine kinase, which may be used as a biomarker for myotoxic activity evaluation [4, 5]. The high medical-scientific concern evoked by the involvement of these proteins in different physiopathological processes promoted an increasing search for natural or *Address correspondence to this author at the FCFRP-USP, Ribeirão Preto- SP, Brasil; Fax: 55-16-3602-4725; E-mail: andreims@fcfrp.usp.br artificial inhibitors, aiming at PLA 2 s neutralization, and a better understanding of their mechanism of action and their structure-function relationship. Different venom toxins can be recognized and inhibited by poly or monoclonal antibodies, as well as by some diversified agents including chemicals (EDTA, BPB, and others), as well as animal and vegetal compounds [6-9], such as heparin. Low molecular weight heparin, an anionic natural polysaccharide, showed to be able to inhibit, at least in part, the myotoxic, cytotoxic and edema inducing effects of B. moojeni MjTX-II and B. neuwiedi BnSP-7 venoms and able to abolish the neuromuscular effect of the latter. These data confirmed the hypothesis that the 115-129 C-terminal region of B. asper myotoxin II, named heparin binding region, would be responsible for PLA 2 cytotoxicity and at least in part for its myotoxicity, since this polyanion interacts with this region of the enzyme [9-13]. Some PLA 2 inhibitors may be found in different orga- nisms. Manoalide (A) is a non-steroidal sesquiterpenoid from the marine sponge Luffariella variabilis, while manoalide (B) was artificially synthesized based on its natural analogue. These terpenoids compounds promote irreversible inhibitory effects upon several PLA 2 s from snakes, bees and mammals [14, 15] Aside from traditional knowledge or the popular use, several scientific evidences have pointed to the efficacy of crude extracts or fractions from plants, such as Eclipta