Discovery, Characterization, and Engineering of LvIC, an α4/4-Conotoxin That Selectively Blocks Rat α6/α3β4 Nicotinic Acetylcholine Receptors

• DOI: 10.1021/acs.jmedchem.2c01786
• Publication Date: 2023-01-22T14:50:17Z
• Authors: Xiaopeng Zhu; Shuai Wang; Quentin Kaas; Jinpeng Yu; Yong Wu; Peta J. Harvey; Dongting Zhangsun; David J. Craik; Sulan Luo
• Keywords: Conotoxin; Nicotinic Antagonist

α6β4 nicotinic acetylcholine receptors (nAChRs) are expressed in the central and peripheral nervous systems, but their functions not fully understood, largely because of a lack specific ligands. Here, we characterized novel α-conotoxin, LvIC, designed series analogues to probe structure–activity relationships at nAChR. The potency selectivity these conotoxins were tested using two-electrode voltage-clamp recording on nAChR subtypes Xenopus laevis oocytes. One analogues, [D1G,ΔQ14]LvIC, potently blocked α6/α3β4 nAChRs (α6/α3 is chimera) with an IC50 19 nM, minimal activity other subtypes, including structurally similar α6/α3β2β3 α3β4 subtypes. Using NMR, molecular docking, receptor mutation, [D1G,ΔQ14]LvIC defined. It potent antagonist that could potentially serve as explore nAChR-related neurophysiological pharmacological functions.