TY - JOUR
T1 - Molecular basis of toxicity of N-type calcium channel inhibitor MVIIA
AU - Wang, Fei
AU - Yan, Zhenzhen
AU - Liu, Zhuguo
AU - Wang, Sheng
AU - Wu, Qiaoling
AU - Yu, Shuo
AU - Ding, Jiuping
AU - Dai, Qiuyun
PY - 2016/2
Y1 - 2016/2
N2 - 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 Met12 in the loop 2, and this residue inserts into a hydrophobic hole (Ile300, Phe302 and Leu305) located between repeats II and III of Cav2.2. The combinative mutations of the loop 2 of MVIIA or other ω-conopeptides may be used for future development of more effective Cav2.2 inhibitors with lower side effects.
AB - 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 Met12 in the loop 2, and this residue inserts into a hydrophobic hole (Ile300, Phe302 and Leu305) located between repeats II and III of Cav2.2. The combinative mutations of the loop 2 of MVIIA or other ω-conopeptides may be used for future development of more effective Cav2.2 inhibitors with lower side effects.
KW - MVIIA
KW - N-type-calcium channel inhibitor
KW - SO-3
KW - Toxicity
KW - ω-conotoxins
UR - http://www.scopus.com/inward/record.url?scp=84942278701&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2015.08.047
DO - 10.1016/j.neuropharm.2015.08.047
M3 - Article
C2 - 26344359
AN - SCOPUS:84942278701
SN - 0028-3908
VL - 101
SP - 137
EP - 145
JO - Neuropharmacology
JF - Neuropharmacology
ER -