A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain
Transmembrane Ca(v)2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca(v)2.2 (e.g., with Prialt/Ziconotide) or indirect modulation [e.g., with gabapentinoids such as Gabapentin (GBP)] mitigates chronic pa...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666126/ https://www.ncbi.nlm.nih.gov/pubmed/37972067 http://dx.doi.org/10.1073/pnas.2305215120 |
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author | Gomez, Kimberly Santiago, Ulises Nelson, Tyler S. Allen, Heather N. Calderon-Rivera, Aida Hestehave, Sara Rodríguez Palma, Erick J. 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 Handoko 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 |
author_facet | Gomez, Kimberly Santiago, Ulises Nelson, Tyler S. Allen, Heather N. Calderon-Rivera, Aida Hestehave, Sara Rodríguez Palma, Erick J. 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 Handoko 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 |
author_sort | Gomez, Kimberly |
collection | PubMed |
description | Transmembrane Ca(v)2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca(v)2.2 (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 Ca(v)2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Ca(v)2.2–CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A(1)R(2) dipeptide in CBD3 as the anchoring Ca(v)2.2 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 Ca(v)2.2 from CRMP2, reduced membrane Ca(v)2.2 expression and Ca(2+) 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 Ca(v)2.2 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. |
format | Online Article Text |
id | pubmed-10666126 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-106661262023-11-16 A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain Gomez, Kimberly Santiago, Ulises Nelson, Tyler S. Allen, Heather N. Calderon-Rivera, Aida Hestehave, Sara Rodríguez Palma, Erick J. 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 Handoko 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 Proc Natl Acad Sci U S A Biological Sciences Transmembrane Ca(v)2.2 (N-type) voltage-gated calcium channels are genetically and pharmacologically validated, clinically relevant pain targets. Clinical block of Ca(v)2.2 (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 Ca(v)2.2 to the sensory neuron membrane and regulates their function via an intrinsically disordered motif. A CRMP2-derived peptide (CBD3) uncouples the Ca(v)2.2–CRMP2 interaction to inhibit calcium influx, transmitter release, and pain. We developed and applied a molecular dynamics approach to identify the A(1)R(2) dipeptide in CBD3 as the anchoring Ca(v)2.2 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 Ca(v)2.2 from CRMP2, reduced membrane Ca(v)2.2 expression and Ca(2+) 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 Ca(v)2.2 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. National Academy of Sciences 2023-11-16 2023-11-21 /pmc/articles/PMC10666126/ /pubmed/37972067 http://dx.doi.org/10.1073/pnas.2305215120 Text en Copyright © 2023 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Gomez, Kimberly Santiago, Ulises Nelson, Tyler S. Allen, Heather N. Calderon-Rivera, Aida Hestehave, Sara Rodríguez Palma, Erick J. 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 Handoko 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 A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title | A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title_full | A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title_fullStr | A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title_full_unstemmed | A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title_short | A peptidomimetic modulator of the Ca(V)2.2 N-type calcium channel for chronic pain |
title_sort | peptidomimetic modulator of the ca(v)2.2 n-type calcium channel for chronic pain |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10666126/ https://www.ncbi.nlm.nih.gov/pubmed/37972067 http://dx.doi.org/10.1073/pnas.2305215120 |
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