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

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Wang F, Yan Z, Liu Z, Wang S, Wu Q, Yu S, Ding J, Dai Q

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

Neuropharmacology. 2016 Feb;101:137-45. doi: 10.1016/j.neuropharm.2015.08.047. Epub 2015 Sep 4.

PubMed ID

26344359 [ View in PubMed

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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, omega-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 repeats II and III of Cav2.2. The combinative mutations of the loop 2 of MVIIA or other omega-conopeptides may be used for future development of more effective Cav2.2 inhibitors with lower side effects.

DrugBank Data that Cites this Article

Drugs

Ziconotide

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Ziconotide	Voltage-dependent N-type calcium channel subunit alpha-1B	Protein	Humans	Yes	Inhibitor	Details
Ziconotide	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Protein	Humans	No	Inhibitor	Details