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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2023
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.
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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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