The E15R Point Mutation in Scorpion Toxin Cn2 Uncouples Its Depressant and Excitatory Activities on Human NaV1.6
Journal of Medicinal Chemistry Go to journalAuthor(s):
Mathilde R. Israel, Panumart Thongyoo, Jennifer R. Deuis, David J. Craik, Irina Vetter, Thomas Durek
We report the chemical synthesis of scorpion toxin Cn2, a potent and highly selective activator of the human voltage-gated sodium channel NaV1.6. In an attempt to decouple channel activation from channel binding, we also synthesized the first analogue of this toxin, Cn2[E15R]. This mutation caused uncoupling of the toxin’s excitatory and depressant activities, effectively resulting in a NaV1.6 inhibitor. In agreement with the in vitro observations, Cn2[E15R] is antinociceptive in mouse models of NaV1.6-mediated pain.