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

Kimberly Gomez, Ulises Santiago, Tyler S. Nelson, Heather N. Allen, Aida Calderon-Rivera, Sara Hestehave, Erick J. Rodríguez Palma, Yuan Zhou, Paz Duran, Santiago Loya-Lopez, Elaine Zhu, Upasana Kumar, Rory Shields, Eda Koseli, Bryan McKiver, Denise Giuvelis, Wanhong Zuo, Kufreobong E. Inyang, Angie Dorame, Aude ChefdevilleDongzhi Ran, Samantha Perez-Miller, Yi Lu, Xia Liu, Handoko, Paramjit S. Arora, Marcel Patek, Aubin Moutal, May Khanna, Huijuan Hu, Geoffroy Laumet, Tamara King, Jing Wang, M. Imad Damaj, Olga A. Korczeniewska, Carlos J. Camacho, Rajesh Khanna

Research output: Contribution to journalArticlepeer-review

Abstract

Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Cav2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pain but is encumbered by side effects and abuse liability. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2–CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A1R2 dipeptide in CBD3 as the anchoring Cav2.2 motif and designed pharmacophore models to screen 27 million compounds on the open-access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization‐evoked calcium influx in rat dorsal root ganglion neurons. Nine small molecules were tested electrophysiologically, while one (CBD3063) was also evaluated biochemically and behaviorally. CBD3063 uncoupled Cav2.2 from CRMP2, reduced membrane Cav2.2 expression and Ca2+ currents, decreased neurotransmission, reduced fiber photometry-based calcium responses in response to mechanical stimulation, and reversed neuropathic and inflammatory pain across sexes in two different species without changes in sensory, sedative, depressive, and cognitive behaviors. CBD3063 is a selective, first-in-class, CRMP2-based peptidomimetic small molecule, which allosterically regulates Cav2.2 to achieve analgesia and pain relief without negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief.

Original languageEnglish (US)
Article numbere2305215120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number47
DOIs
StatePublished - 2023
Externally publishedYes

Keywords

  • Ca2.2
  • analgesia
  • chronic pain
  • electrophysiology
  • peptidomimetic

ASJC Scopus subject areas

  • General

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