PeIA-5466: A Novel Peptide Antagonist Containing Non-natural Amino Acids That Selectively Targets ?3?2 Nicotinic Acetylcholine Receptors.

ABSTRACT: Pharmacologically distinguishing ?3?2 nicotinic acetylcholine receptors (nAChRs) from closely related subtypes, particularly ?6?2, has been challenging due to the lack of subtype-selective ligands. We created analogs of ?-conotoxin (?-Ctx) PeIA to identify ligand-receptor interactions that could be exploited to selectively increase potency and selectivity for ?3?2 nAChRs. A series of PeIA analogs were synthesized by replacing amino acid residues in the second disulfide loop with standard or nonstandard residues and assessing their activity on ?3?2 and ?6/?3?2?3 nAChRs heterologously expressed in Xenopus laevis oocytes. Asparagine11 was found to occupy a pivotal position, and when replaced with negatively charged amino acids, selectivity for ?3?2 over ?6/?3?2?3 nAChRs was substantially increased. Second generation peptides were then designed to further improve both potency and selectivity. One peptide, PeIA-5466, was ?300-fold more potent on ?3?2 than ?6/?3?2?3 and is the most ?3?2-selective antagonist heretofore reported.

SUBMITTER: Hone AJ 

PROVIDER: S-EPMC7342494 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature