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

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

作者地址："[Gomez, Kimberly; Nelson, Tyler S.; Allen, Heather N.; Calderon-Rivera, Aida; Hestehave, Sara; Palma, Erick J. Rodriguez; Duran, Paz; Loya-Lopez, Santiago; Perez-Miller, Samantha; Khanna, May; Khanna, Rajesh] NYU, Coll Dent, Dept Mol Pathobiol, New York, NY 10010 USA; [Gomez, Kimberly; Nelson, Tyler S.; Allen, Heather N.; Calderon-Rivera, Aida; Hestehave, Sara; Palma, Erick J. Rodriguez; Duran, Paz; Loya-Lopez, Santiago; Perez-Miller, Samantha; Khanna, May; Khanna, Rajesh] NYU, Pain Res Ctr, New York, NY 10010 USA; [Santiago, Ulises; Camacho, Carlos J.] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA; [Zhou, Yuan; Dorame, Angie; Chefdeville, Aude] Univ Arizona, Coll Med, Dept Pharmacol, Tucson, AZ 85724 USA; [Zhu, Elaine; Wang, Jing] NYU, Dept Anesthesiol Perioperat Care & Pain Med, Grossman Sch Med, New York, NY 10016 USA; [Zhu, Elaine; Wang, Jing] NYU, Interdisciplinary Pain Res Program, Langone Hlth, New York, NY 10016 USA; [Kumar, Upasana; Korczeniewska, Olga A.] Rutgers Sch Dent Med, Ctr Orofacial Pain & Temporomandibular Disorders, Dept Diagnost Sci, Newark, NJ 07101 USA; [Shields, Rory; Korczeniewska, Olga A.] Rutgers Sch Grad Studies, Newark Hlth Sci Campus, Newark, NJ 07101 USA; [Koseli, Eda; McKiver, Bryan; Damaj, M. Imad] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA; [Koseli, Eda; McKiver, Bryan; Damaj, M. Imad] Virginia Commonwealth Univ, Translat Res Initiat Pain & Neuropathy, Richmond, VA 23298 USA; [Giuvelis, Denise; King, Tamara] Univ New England, Coll Osteopath Med, Ctr Excellence Neurosci, Dept Biomed Sci, Biddeford, ME 04005 USA; [Zuo, Wanhong; Hu, Huijuan] Rutgers New Jersey Med Sch, Dept Anesthesiol, Newark, NJ 07103 USA; [Inyang, Kufreobong E.; Laumet, Geoffroy] Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA; [Ran, Dongzhi; Lu, Yi; Liu, Xia] Chongqing Med Univ, Sch Pharm, Dept Pharmacol, Chongqing 400016, Peoples R China; [Handokon; Arora, Paramjit S.] NYU, Dept Chem, New York, NY 10003 USA; [Patek, Marcel] Bright Rock Path Ltd Liabil Co, Tucson, AZ 85724 USA; [Moutal, Aubin] St Louis Univ, Sch Med, Dept Pharmacol & Physiol, St Louis, MO 63104 USA; [Wang, Jing; Khanna, Rajesh] NYU, Sch Med, Dept Neurosci & Physiol, New York, NY 10010 USA; [Wang, Jing; Khanna, Rajesh] NYU, Neurosci Inst, Sch Med, New York, NY 10010 USA; [Khanna, Rajesh] NYU, Tandon Sch Engn, Chem & Biomol Engn Dept, New York, NY 11201 USA"

通信作者："Khanna, R (通讯作者)，NYU, Coll Dent, Dept Mol Pathobiol, New York, NY 10010 USA.; Khanna, R (通讯作者)，NYU, Pain Res Ctr, New York, NY 10010 USA.; Camacho, CJ (通讯作者)，Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15261 USA.; Khanna, R (通讯作者)，NYU, Sch Med, Dept Neurosci & Physiol, New York, NY 10010 USA.; Khanna, R (通讯作者)，NYU, Neurosci Inst, Sch Med, New York, NY 10010 USA.; Khanna, R (通讯作者)，NYU, Tandon Sch Engn, Chem & Biomol Engn Dept, New York, NY 11201 USA."

来源：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

ESI学科分类：Multidisciplinary

WOS号：WOS:001137071000011

JCR分区：Q1

影响因子：9.4

年份：2023

卷号：120

期号：47

开始页：　

结束页：　

文献类型：Article

关键词：Cav2.2; peptidomimetic; electrophysiology; chronic pain; analgesia

摘要："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 with-out negative side effect profiles. In summary, CBD3063 could potentially be a more effective alternative to GBP for pain relief."

基金机构："NIH [NINDS NS098772, NS120663, NIDA DA042852]; NINDS [NS119263, NS121259, GM115384]; NIGMS [NS121776, P30GM145497]; Rita Allen Foundation; NCI [R01CA219637]"

基金资助正文："Supported by NIH awards (NINDS NS098772 and NS120663, NIDA DA042852 to R.K.) ; A.M. by NINDS NS119263;J.W. by NIGMS GM115384 and NINDS NS121776; G.L. by the Rita Allen Foundation and NINDS NS121259; T.K. by NIGMS P30GM145497 to Ian Meng; and M.I.D. by NCI R01CA219637. All data are available in the main text, figures, SIAppendix."