Synthesis and Biological Activity of Novel a-Conotoxin Analogues Incorporating Substituted Proline Derivatives

摘要

alpha-Conotoxins are peptide neurotoxins, which are potent and selective inhibitors of neuronal nicotinic acetylcholine receptors (nAChRs)[l]. They are characterised by the presence of two disulfide bonds and a highly conserved proline residue (Pro6) that contributes to their well defined 3D structures (Figure 1). Acetylcholine binding protein from Aplysia californica (Ac-AChBP) shares sequence homology with the ligand binding domain of nAChRs, thus provides insight for the rational design of new analogues with improved pharmacology. Recent crystal structures of a-conotoxins Iml and PnIA[A10L,D14K] complexed with Ac-AChSP provide further insight of ligand binding at the molecular level [2, 3]. These show that upon binding, the side chain of Pro6 is oriented towards the hydrophobic binding pocket in AChBP (Figure 2). We propose that additional interactions with the hydrophobic binding pocket could be gained through introduction of substituents on the proline side-chain without perturbing the overall fold of the peptide. Further experimental data into the role of specific amino acids in the nAChR will provide further insight into alpha-conotoxin / alpha 7 nAChR binding.