Chemistry of Snake Neurotoxins and Future Perspectives

A historical review on the study of snake neurotoxins is presented, with special emphasis on the author's contributions in unraveling the chemistry of one of the most lethal non‐enzymatic protein factors. Cobrotoxin, a postsynaptic neurotoxin isolated in a crystalline state from the venom of Taiwan cobra, binds specifically to the nicotinic acetylcholine receptors on the postsynaptic membrane and thus blocks the neuromuscular transmission. It is a small basic protein consisting of a single peptide chain of 62 aminoacid residues, crosslinked by four disulfide bonds. The disulfide bonds and Tyr‐25 which are buried in the molecule form a central core to maintain and stabilize the active conformation of the toxin. Selective and stepwise chemical modifications of cobrotoxin indicate that at least two cationic groups, an ϵ‐amino group of Lys‐47 and a guanidino group of Arg‐33, both of which are common to all known postsynaptic snake neurotoxins, held at a certain critical distance in the molecule, are functionally important for its neuromuscular blocking activity. Neurotoxins of another type exist in some common cobras or sea snakes. These presynaptic neurotoxins are basic phospholipase A2 (PLA2) per se or contain basic PLA2 as an indispensable part of their structures. Presynaptic PLA2 neurotoxins show both PLA2 activity and presynaptic neurotoxicity. Chemical modification of two highly potent presynaptic neurotoxins β1‐bungarotoxin and notexin was undertaken in the hope of elucidating the molecular features contributing to the biological activities of presynaptic PLA2 neurotoxins. Modification of tyrosine residues differentially influences the enzymatic activity and lethal toxicity of β1‐bungarotoxin and notexin, revealing that these toxins might possess two functional sites, one being responsible for the catalytic activity and the other for their pharmacological properties.