conotoxin-gv and Nervous-System-Diseases

Conus peptides comprise a diverse class of bioactive molecules, each of which is believed to have a biological target. From the 50,000 plus molecules thought to exist, several groups are judged to have potential neuroprotective activity. Those that block voltage-gated calcium channels were seen as most promising, but this is now in some doubt. Those that act at NMDA receptors may be able to protect against acute and chronic assault, while those acting at nicotinic receptors or at potassium channels seem mainly to have potential against chronic assault. The poor pharmacokinetic profile of the peptides remains a challenge.

Topics: Animals; Calcium Channel Blockers; Clinical Trials, Phase III as Topic; Conotoxins; Drug Evaluation, Preclinical; Humans; Nervous System Diseases; Neuroprotective Agents; omega-Conotoxins; Potassium Channels, Voltage-Gated; Snails

Calcium flow through the ion channel of the N-methyl-D-aspartate receptor (NMDAR) has been implicated as contributing to a variety of neuropathologies. This receptor is a complex heteromeric oligomer consisting of different types of subunits, the nature of which governs its properties, as well as its response to a variety of agonists, antagonists, and other types of inhibitors. A new natural series of NMDAR inhibitors, the conantokins, have been shown to be present in the venoms of snails within the genus, Conus. These agents appear to function by inhibition of the spermine/spermidine stimulation of ion flow through the NMDAR channel. These small peptides (17-27 amino acid residues) are highly processed post-translationally. One such processing event is the vitamin K-dependent gamma-carboxylation of glutamate, resulting in placement of gamma-carboxyglutamic acid residues in these peptides. As a result, these peptides then possess the ability to interact with divalent metal ions and concomitantly undergo a conformational alteration. Rational drug design based on the characteristics of these promising peptides requires knowledge of their properties and the manner in which they target the NMDAR. This review summarizes current knowledge in this area.

Topics: Animals; Calcium; Conotoxins; Excitatory Amino Acid Antagonists; Humans; Intercellular Signaling Peptides and Proteins; Ion Channel Gating; Mollusk Venoms; Nervous System Diseases; Peptides; Receptors, N-Methyl-D-Aspartate; Spermine; Structure-Activity Relationship