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

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

  • Proc Natl Acad Sci U S A. 2023 Nov 21;120(47):e2305215120. doi: 10.1073/pnas.2305215120.
Kimberly Gomez # 1 2,  Ulises Santiago # 3,  Tyler S Nelson 1 2,  Heather N Allen 1 2,  Aida Calderon-Rivera 1 2,  Sara Hestehave 1 2,  Erick J Rodríguez Palma 1 2,  Yuan Zhou 4,  Paz Duran 1 2,  Santiago Loya-Lopez 1 2,  Elaine Zhu 5 6,  Upasana Kumar 7,  Rory Shields 8,  Eda Koseli 9,  Bryan McKiver 9,  Denise Giuvelis 10,  Wanhong Zuo 11,  Kufreobong E Inyang 12,  Angie Dorame 4,  Aude Chefdeville 4,  Dongzhi Ran 13,  Samantha Perez-Miller 1 2,  Yi Lu 13,  Xia Liu 13,  Handoko 14,  Paramjit S Arora 14,  Marcel Patek 15,  Aubin Moutal 16,  May Khanna 1 2,  Huijuan Hu 11,  Geoffroy Laumet 12,  Tamara King 10,  Jing Wang 5 6 17,  M Imad Damaj 9,  Olga A Korczeniewska 7 8,  Carlos J Camacho 3,  Rajesh Khanna 1 2 17 18
Affiliations

Affiliations

  • 1 Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY 10010.
  • 2 New York University Pain Research Center, New York, NY 10010.
  • 3 Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261.
  • 4 Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ 85724.
  • 5 Department of Anesthesiology, Perioperative Care and Pain Medicine, New York University Grossman School of Medicine, New York, NY 10016.
  • 6 Interdisciplinary Pain Research Program, New York University Langone Health, New York, NY 10016.
  • 7 Department of Diagnostic Sciences, Center for Orofacial Pain and Temporomandibular Disorders, Rutgers School of Dental Medicine, Newark, NJ 07101.
  • 8 Rutgers School of Graduate Studies, Newark Health Science Campus, Newark, NJ 07101.
  • 9 Department of Pharmacology and Toxicology and Translational Research Initiative for Pain and Neuropathy, Virginia Commonwealth University, Richmond, VA 23298.
  • 10 Department of Biomedical Sciences, College of Osteopathic Medicine, Center for Excellence in the Neurosciences, University of New England, Biddeford, ME 04005.
  • 11 Department of Anesthesiology, Rutgers New Jersey Medical School, Newark, NJ 07103.
  • 12 Department of Physiology, Michigan State University, East Lansing, MI 48824.
  • 13 Department of Pharmacology, School of Pharmacy, Chongqing Medical University, Chongqing 400016, China.
  • 14 Department of Chemistry, New York University, New York, NY 10003.
  • 15 Bright Rock Path Limited Liability Company, Tucson, AZ 85724.
  • 16 Department of Pharmacology and Physiology, School of Medicine, St. Louis University, St. Louis, MO 63104.
  • 17 Department of Neuroscience and Physiology and Neuroscience Institute, School of Medicine, New York University, New York, NY 10010.
  • 18 Chemical, and Biomolecular Engineering Department, Tandon School of Engineering, New York University, New York City, NY 11201.
  • # Contributed equally.
PMID: 37972067 DOI: 10.1073/pnas.2305215120
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.

Keywords

Cav2.2; analgesia; chronic pain; electrophysiology; peptidomimetic.

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