Marine cone snail venoms consist of large naturally occuring combinatorial libraries of disulfide rich polypeptides known as conotoxins that encompass a vast array of neuropharmacological activities. As such, they are valuable as research tools and drug leads for targeting the central nervous system. Conotoxins are characterized by conserved disulfide bond frameworks that give rise to intervening loops of hypervariable amino acids that determine their exquisite pharmacological function. We have developed a synthetic combinatorial strategy that utilizes the hypervariable regions of a-conotoxins to discover novel nicotinic acetylcholine receptor antagonists with unique receptor subtype selectivity profiles for studying tobacco addiction and pain. Central to this strategy are positional-scanning synthetic combinatorial libraries (PS-SCLs), which allow functional amino acid residues to be directly identified from synthetic mixtures using direct in vitro and in vivo screening and deconvolution. This approach greatly accelerates the discovery of novel ligands for use as research tools and drug leads.

Synthetic α-conotoxin mixture-based combinatorial libraries for discovering novel research tools and drugs leads for studying tobacco addiction and pain

245th National Meeting (2013)

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