Natural inhibitors of toxic phospholipases A(2).

Endogenous proteins isolated from the serum of snakes have been found to be natural inhibitors displaying anti-hemorrhagic, anti-neurotoxic or anti-myotoxic activity. Some of these proteins inhibit phospholipase A(2) (PLA(2)) activity. We review in brief here the properties, structure and classification of these PLA(2) inhibitors (PLIs), focusing in particular on the mechanism of neutralization of the toxic PLA(2)s by anti-neurotoxic PLIs. We also discuss: 1) the protection provided by these molecules against endogenous snake venom PLA(2)s; 2) their specificity for neurotoxic snake venom PLA(2)s (beta-neurotoxins) and non-toxic mammalian secreted sPLA(2)s; and 3) the domains of the inhibitor and PLA(2) potentially involved in the binding of these two molecules. Purified and characterized natural inhibitors of PLA(2)s may be used to develop more effective therapeutic strategies for dealing with snake envenomation. Moreover, the structural and, in some cases, functional similarity of natural inhibitors to various mammalian proteins suggests that these mammalian proteins may themselves behave as PLA(2) inhibitors. Thus, these proteins may have important physiological functions in regulating the activities of neurotoxic PLA(2) and non-toxic sPLA(2).