Engineered Conotoxin Differentially Blocks and Discriminates Rat and Human α7 Nicotinic Acetylcholine Receptors.

Shuai Wang, Xiaopeng Zhu, Manqi Zhangsun, Yong Wu, Jinpeng Yu, Peta J Harvey, Quentin Kaas, Dongting Zhangsun, David J Craik, Sulan Luo

Journal of medicinal chemistry 2021 May 13

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The α7 nicotinic acetylcholine receptor (nAChR) is present in the central nervous system and plays an important role in cognitive function and memory. α-Conotoxin LvIB, identified from genomic DNA of Conus lividus, its three isomers and four globular isomer analogues were synthesized and screened at a wide range of nAChR subtypes. One of the analogues, amidated [Q1G,ΔR14]LvIB, was found to be a potent blocker of rat α7 nAChRs. Importantly, it differentiates between α7 nAChRs of human (IC50: 1570 nM) and rat (IC50: 97 nM). Substitutions between rat and human α7 nAChRs at three key mutation sites revealed that no single mutant could completely change the activity profile of amidated [Q1G,ΔR14]LvIB. Rather, we found that the combined influence of Gln141, Asn184, and Lys186 determines the α7 nAChR species specificity of this peptide. This engineered α4/4 conotoxin has potential applications as a template for designing ligands to selectively block human α7 nAChRs.

Citation

Shuai Wang, Xiaopeng Zhu, Manqi Zhangsun, Yong Wu, Jinpeng Yu, Peta J Harvey, Quentin Kaas, Dongting Zhangsun, David J Craik, Sulan Luo. Engineered Conotoxin Differentially Blocks and Discriminates Rat and Human α7 Nicotinic Acetylcholine Receptors. Journal of medicinal chemistry. 2021 May 13;64(9):5620-5631