Screening, synthesis and structural characterization of a novel bicyclic peptide inhibiting α7 nicotinic acetylcholine receptor.

Peptides targeting the α7 nicotinic acetylcholine receptor (α7-nAChR) represent promising candidates for therapeutic and chemical probe development. Here, we identified a novel bicyclic peptide KP1877 via phage-displayed peptide library screening followed by chemical synthesis of active analogs. Structural characterization reveals KP1877 adopts a unique bicyclic conformation distinct from known natural α7-nAChR-targeting peptides, and exerts potent inhibitory effect by stabilizing the closed, non-conducting state of the receptor via orthosteric binding.