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Rationally Designed α-Conotoxin Analogues Maintained Analgesia Activity and Weakened Side Effects

State Key Laboratory of Natural Medicines, Ministry of Education, The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, Department of Marine Pharmacy, China Pharmaceutical University, Nanjing 211198, China
Mason Laboratory, Department of Mechanical Engineering & Materials Science, Yale University, New Haven, CT 06520, USA
State key laboratory of mechanics and control of mechanical structures, Department of Aerocraft Design, College of Aerospace Engineering, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China
Department of Pharmacy, University of Naples Federico II, Naples, 49 80131 Via D. Montesano, Italy
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Molecules 2019, 24(2), 337;
Received: 13 December 2018 / Revised: 5 January 2019 / Accepted: 17 January 2019 / Published: 18 January 2019
(This article belongs to the Section Medicinal Chemistry)
PDF [2413 KB, uploaded 18 January 2019]


A lack of specificity is restricting the further application of conotoxin from Conus bullatus (BuIA). In this study, an analogue library of BuIA was established and virtual screening was used, which identified high α7 nicotinic acetylcholine receptor (nAChR)-selectivity analogues. The analogues were synthesized and tested for their affinity to functional human α7 nAChR and for the regulation of intracellular calcium ion capacity in neurons. Immunofluorescence, flow cytometry, and patch clamp results showed that the analogues maintained their capacity for calcium regulation. The results of the hot-plate model and paclitaxel-induced peripheral neuropathy model indicated that, when compared with natural BuIA, the analgesia activities of the analogues in different models were maintained. To analyze the adverse effects and toxicity of BuIA and its analogues, the tail suspension test, forced swimming test, and open field test were used. The results showed that the safety and toxicity of the analogues were significantly better than BuIA. The analogues of BuIA with an appropriate and rational mutation showed high selectivity and maintained the regulation of Ca2+ capacity in neurons and activities of analgesia, whereas the analogues demonstrated that the adverse effects of natural α-conotoxins could be reduced. View Full-Text
Keywords: conotoxin; nAChR; analgesia; side effects conotoxin; nAChR; analgesia; side effects

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Liu, C.; Wu, P.; Zhu, H.; Grieco, P.; Yu, R.; Gao, X.; Wu, G.; Wang, D.; Xu, H.; Qi, W. Rationally Designed α-Conotoxin Analogues Maintained Analgesia Activity and Weakened Side Effects. Molecules 2019, 24, 337.

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