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A rationally designed peptidomimetic modulator of CaV2.2 (N-type) voltage-gated calcium channels for chronic pain
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  • Kimberly Gomez,
  • Ulises Santiago,
  • Paz Duran,
  • Yuan Zhou,
  • Aida Calderon,
  • Santiago Loya-López,
  • Angie Dorame,
  • Aude Chefdeville,
  • Aubin Moutal,
  • Dongzhi Ran,
  • Samantha Perez-Miller,
  • Yi Lu,
  • Xia Liu,
  • Handoko Handoko,
  • Paramjit Arora,
  • Marcel Patek,
  • Carlos J. Camacho,
  • Rajesh Khanna
Kimberly Gomez
New York University

Corresponding Author:kg3145@nyu.edu

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Ulises Santiago
University of Pittsburgh
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Paz Duran
New York University
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Yuan Zhou
University of Arizona
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Aida Calderon
New York University
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Santiago Loya-López
New York University
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Angie Dorame
University of Arizona Medical Center - University Campus
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Aude Chefdeville
University of Arizona
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Aubin Moutal
University of Arizona Medical Center - University Campus
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Dongzhi Ran
University of Arizona Medical Center - University Campus
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Samantha Perez-Miller
University of Arizona
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Yi Lu
Chongqing Medical University
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Xia Liu
Chongqing Medical University
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Handoko Handoko
New York University
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Paramjit Arora
New York University
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Marcel Patek
Bright Rock Path LLC
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Carlos J. Camacho
University of Pittsburgh
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Rajesh Khanna
New York University
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Abstract

Background and Purpose Transmembrane Cav2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated pain targets. Clinical block of Cav2.2 (e.g., with Prialt) or indirect modulation (e.g., with gabapentinoids) mitigates chronic pain but is constrained by side effects. The cytosolic auxiliary subunit collapsin response mediator protein 2 (CRMP2) targets Cav2.2 to the sensory neuron membrane and regulates their function. A CRMP2-derived peptide (CBD3) uncouples the Cav2.2-CRMP2 interaction to inhibit calcium influx, transmitter release and pain. Homology-guided mutagenesis of CBD3 revealed an antinociceptive core at A1RSR4. Here, the A1R2 CBD3 dipeptide was identified as critical for Cav2.2 molecular recognition and served as a scaffold for identification of small molecule peptidomimetic allosteric regulators of Cav2.2. Experimental Approach We developed and applied a novel molecular dynamics approach to identify the Cav2.2 recognition motif of the core CBD3 peptide as the A1R2 dipeptide and used its presenting motif to design pharmacophore models to screen 27 million compounds in the open access server ZincPharmer. Of 200 curated hits, 77 compounds were assessed using depolarization‐evoked calcium influx in rat dorsal root ganglion (DRG) neurons. Nine compounds were tested using electrophysiology and one compound (CBD3063) was evaluated biochemically, electrophysiologically, and behaviorally effects in a model of experimental pain: Key Results CBD3063 reduced membrane Cav2.2 expression and currents, inhibited neuronal excitability, uncoupled the Cav2.2-CRMP2 interaction, and reversed mechanical allodynia in rats with spared nerve injury. Conclusions and Implications These results identify CBD3063, as a selective, first-in-class, CRMP2-based peptidomimetic, which allosterically regulates Cav2.2 to achieve analgesia.