Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors

What is it about?

Voltage-gated sodium channel (Nav) subtypes are involved in nociception and signal transduction in the central and peripheral nervous system, and in skeletal and cardiac muscle function. We show that it is possible to define peptide toxins targeting Nav to a minimal pharmacophore and that cyclization of these minimized peptides greatly enhance their biopharmaceutical properties. To achieve this, we combined the sophisticated peptide chemistry of spiders and cone snails. The resulting 13 residue cyclic peptide retained potent Nav activity but displayed impressively increased serum stability. The obtained peptides represent the first and the smallest cyclic peptide Nav modulators to date and are thus promising templates in the development of novel therapeutic agents for treatment of Nav channel related diseases.

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