A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain

Abstract

Transmembrane Ca_v2.2 voltage-gated calcium channels play a central role in pain through providing the Ca²⁺ for sustained neuronal firing and neurotransmitter release. Therapeutics targeting Ca_v2.2 include the blocking peptide toxin Ziconotide and the gabapentinoids (e.g., Gabapentin), which target an auxiliary subunit of Ca_v2.2; however, both drugs are encumbered with numerous side effects. Collapsin response mediator protein 2 (CRMP2) is key cytosolic regulator of Ca_v2.2. CBD3063, a novel peptidomimetic we devised, selectively curbs Ca_v2.2 activity, paralleling Gabapentin in alleviating neuropathic and inflammatory pain across sexes. In contrast to Gabapentin, CBD3063 upheld the protective/adaptive role of pain, without negatively affecting sedative, depressive, or cognitive behaviors. In short, CBD3063 may be a superior successor in pain management.