Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA

Neuropharmacology
Fei WangQiuyun Dai

Abstract

MVIIA (ziconotide) is a specific inhibitor of N-type calcium channel, Cav2.2. It is derived from Cone snail and currently used for the treatment of severe chronic pains in patients unresponsive to opioid therapy. However, MVIIA produces severe side-effects, including dizziness, nystagmus, somnolence, abnormal gait, and ataxia, that limit its wider application. We previously identified a novel inhibitor of Cav2.2, ω-conopeptide SO-3, which possesses similar structure and analgesic activity to MVIIA's. To investigate the key residues for MVIIA toxicity, MVIIA/SO-3 hybrids and MVIIA variants carrying mutations in its loop 2 were synthesized. The substitution of MVIIA's loop 1 with the loop 1 of SO-3 resulted in significantly reduced Cav2.2 binding activity in vitro; the replacement of MVIIA loop 2 by the loop 2 of SO-3 not only enhanced the peptide/Cav2.2 binding but also decreased its toxicity on goldfish, attenuated mouse tremor symptom, spontaneous locomotor activity, and coordinated locomotion function. Further mutation analysis and molecular calculation revealed that the toxicity of MVIIA mainly arose from Met(12) in the loop 2, and this residue inserts into a hydrophobic hole (Ile(300), Phe(302) and Leu(305)) located between...Continue Reading

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Citations

Oct 26, 2016·Neuropharmacology·Emmanuel Bourinet, Gerald W Zamponi
Jun 14, 2017·British Journal of Pharmacology·Jeffrey R McArthurDavid J Adams
Mar 6, 2019·Marine Drugs·Rachael A MansbachS Gnanakaran
May 15, 2019·Marine Drugs·Shuo YuMingxin Dong
Feb 22, 2021·Toxicon : Official Journal of the International Society on Toxinology·Yuanyuan QiangLei Wang
Mar 21, 2021·Basic & Clinical Pharmacology & Toxicology·Yun WuMaojun Zhou
Oct 4, 2018·Biochemistry·Minxing DongQiuyun Dai
Oct 22, 2019·Chemical Reviews·Ai-Hua JinPaul F Alewood
Nov 11, 2021·Science Translational Medicine·Selwyn JayakarClifford J Woolf

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