A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain
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A peptidomimetic modulator of the CaV2.2 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; Liu, Xia; Handoko; Arora, Paramjit S.; Patek, Marcel; Moutal, Aubin; Khanna, May; Hu, Huijuan; Laumet, Geoffroy; King, Tamara; Damaj, M. Imad; Korczeniewska, Olga A.; Camacho, Carlos J.; Khanna, Rajesh.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 120, No. 47, e2305215120, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A peptidomimetic modulator of the CaV2.2 N-type calcium channel for chronic pain
AU - Gomez, Kimberly
AU - Santiago, Ulises
AU - Nelson, Tyler S.
AU - Allen, Heather N.
AU - Calderon-Rivera, Aida
AU - Hestehave, Sara
AU - Rodríguez Palma, Erick J.
AU - Zhou, Yuan
AU - Duran, Paz
AU - Loya-Lopez, Santiago
AU - Zhu, Elaine
AU - Kumar, Upasana
AU - Shields, Rory
AU - Koseli, Eda
AU - McKiver, Bryan
AU - Giuvelis, Denise
AU - Zuo, Wanhong
AU - Inyang, Kufreobong E.
AU - Dorame, Angie
AU - Chefdeville, Aude
AU - Ran, Dongzhi
AU - Perez-Miller, Samantha
AU - Liu, Xia
AU - Handoko, null
AU - Arora, Paramjit S.
AU - Patek, Marcel
AU - Moutal, Aubin
AU - Khanna, May
AU - Hu, Huijuan
AU - Laumet, Geoffroy
AU - King, Tamara
AU - Damaj, M. Imad
AU - Korczeniewska, Olga A.
AU - Camacho, Carlos J.
AU - Khanna, Rajesh
N1 - Publisher Copyright: Copyright © 2023 the Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
KW - analgesia
KW - Ca2.2
KW - chronic pain
KW - electrophysiology
KW - peptidomimetic
U2 - 10.1073/pnas.2305215120
DO - 10.1073/pnas.2305215120
M3 - Journal article
C2 - 37972067
AN - SCOPUS:85177464612
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 47
M1 - e2305215120
ER -
ID: 388329530