Tobacco addiction is a global public health problem.  Nicotine addiction is mediated through the activation of multiple subtypes of nicotinic acetylcholine receptor (nAChR), among which the a4�2 and a3�4 subtypes have been identified as important targets for developing novel smoking cessation drugs.  a-Conotoxins are disulfide-rich peptides isolated from venomous cone snails. They exhibit exquisite nAChR selectivity and represent excellent structural templates for developing novel pharmacological probes and drug leads.  Here we present the synthesis and functional screening of positional-scanning synthetic combinatorial libraries based on key a-conotoxin structural frameworks against different nAChR subtypes.  Libraries were constructed using the tea bag method with Boc-SPPS and the disulfide bonds formed by co-solvent assisted oxidative folding.  Our data suggests that potent amino acid residues can be identified through iterative deconvolution, thus paving the way for the design of selective nAChR antagonists as chemical probes, with the potential to develop therapeutics for treating tobacco addition.

Selectively targeting nicotinic acetylcholine receptors with α-conotoxin mixture-based combinatorial libraries

245th National Meeting (2013)

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