Development of Conformationally Constrained alpha-RgIA Analogues as Stable Peptide Antagonists of Human alpha 9 alpha 10 Nicotinic Acetylcholine Receptors

摘要

Non-opioid therapeutics for the treatment of neuropathic pain are urgently needed to address the ongoing opioid crisis. Peptides from cone snail venoms have served as invaluable molecules to target key pain-related receptors but can suffer from unfavorable physicochemical properties, which limit their therapeutic potential. In this work, we developed conformationally constrained alpha-RgIA analogues with high potency, receptor selectivity, and enhanced human serum stability to target the human alpha 9 alpha 10 nicotinic acetylcholine receptor. The key lactam linkage introduced in alpha-RgIA fixed the favored globular conformation and suppressed disulfide scrambling. The NMR structure of the macrocyclic peptide overlays well with that of alpha-RgIA4, demonstrating that the cyclization does not perturb the overall conformation of backbone and key side-chain residues. Finally, a molecular docking model was used to rationalize the selective binding between a macrocyclic analogue and the alpha 9 alpha 10 nicotinic acetylcholine receptor. These conformationally constrained antagonists are therefore promising candidates for antinociceptive therapeutic intervention.