J. Michael McIntosh

CHAPTER 6:The Molecular Diversity of Conoidean Venom Peptides and their Targets: From Basic Research to Therapeutic Applications

The >10 000 species of venomous marine snails (superfamily Conoidea) have evolved sophisticated chemical strategies to interact with other animals in their environment. A conoidean venom typically contains 50–200 peptides unique to that species, each honed by natural selection to interact with a specific molecular target in the prey, predators or competitors of the snail. The diversity and molecular targeting specificity of conoidean venom peptides has provided sets of ligands that allow the pharmacological differentiation of different subtypes in large ion channel/receptor families (such as Na channels and nicotinic receptors). Conoidean venoms contain multiple sets of peptides, known as “cabals”, acting in concert on functionally linked molecular targets to achieve a specific physiological end-point, such as paralysis or excitotoxic shock. Each cabal targets a cognate “constellation” of receptors and ion channels in a physiological circuit. For example, the “motor cabal” causes neuromuscular paralysis, with different peptides of the cabal targeting specific motor constellation components, including Ca channels in motor neurons, Na channels and nAChRs in muscle. The elucidation of venom-peptide cabals and receptor/ion-channel constellations has inspired a new pharmacological paradigm called “Constellation Pharmacology” with the potential to transform both the discovery of novel pharmacological agents and the development of therapeutic drugs.

Conus Peptides and Their Iodinated Derivatives as Probes for Ion Channels and Receptors

The genus of venomous marine snails known as Conus has been a very rich resource for the development of biochemical tools in cell biology. Since the isolation of a-conotoxin GI from the venom of the fish-hunting species Conus geographus (Cruz et al., 1978), many other peptides have been purified from its venom. Among these are several peptides that inhibit acetylcholine receptors (α-conotoxins), peptides that block voltage-sensitive sodium channels (μ-conotoxins), peptides which block voltage-sensitive calcium channels (ω-conotoxins), an inhibitor of the NMDA receptor (conantokin-G), and an agonist of the vasopressin receptor (conopressin) (Gray et al., 1988 Olivera et al., 1990; Myers et al., 1993). Examination of the venom components of other species has revealed new classes of peptides with different modes of action.