TY - JOUR
T1 - Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents
AU - Cai, Song
AU - Moutal, Aubin
AU - Yu, Jie
AU - Chew, Lindsey A.
AU - Isensee, Jörg
AU - Chawla, Reena
AU - Gomez, Kimberly
AU - Luo, Shizhen
AU - Zhou, Yuan
AU - Chefdeville, Aude
AU - Madura, Cynthia
AU - Perez-Miller, Samantha
AU - Bellampalli, Shreya Sai
AU - Dorame, Angie
AU - Scott, David D.
AU - François-Moutal, Liberty
AU - Shan, Zhiming
AU - Woodward, Taylor
AU - Gokhale, Vijay
AU - Hohmann, Andrea G.
AU - Vanderah, Todd W.
AU - Patek, Marcel
AU - Khanna, May
AU - Hucho, Tim
AU - Khanna, Rajesh
N1 - Funding Information:
We thank K. B. Gonzalez for performing the chronic dosing experiment, H. Ellingson for performing naïve CPP, and F. Porreca and A. Patwardhan for helpful discussions on this project. Funding: This study was supported by the NIH awards NINDS (NS098772 and NS120663 to R.K.), NIDA (DA042852 to R.K.), and NCI (CA200417 to A.G.H.). T.W. was supported by T32DA024628. Author contributions: R.K. developed the concept,
Publisher Copyright:
Copyright © 2021 The Authors, some rights reserved;
PY - 2021/11/10
Y1 - 2021/11/10
N2 - The voltage-gated sodium NaV1.7 channel, critical for sensing pain, has been actively targeted by drug developers; however, there are currently no effective and safe therapies targeting NaV1.7. Here, we tested whether a different approach, indirect NaV1.7 regulation, could have antinociceptive effects in preclinical models. We found that preventing addition of small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and had antinociceptive effects in rodents. In silico targeting of the SUMOylation site in CRMP2 (Lys374) identified >200 hits, of which compound 194 exhibited selective in vitro and ex vivo NaV1.7 engagement. Orally administered 194 was not only antinociceptive in preclinical models of acute and chronic pain but also demonstrated synergy alongside other analgesics—without eliciting addiction, rewarding properties, or neurotoxicity. Analgesia conferred by 194 was opioid receptor dependent. Our results demonstrate that 194 is a first-in-class protein-protein inhibitor that capitalizes on CRMP2-NaV1.7 regulation to deliver safe analgesia in rodents.
AB - The voltage-gated sodium NaV1.7 channel, critical for sensing pain, has been actively targeted by drug developers; however, there are currently no effective and safe therapies targeting NaV1.7. Here, we tested whether a different approach, indirect NaV1.7 regulation, could have antinociceptive effects in preclinical models. We found that preventing addition of small ubiquitin-like modifier (SUMO) on the NaV1.7-interacting cytosolic collapsin response mediator protein 2 (CRMP2) blocked NaV1.7 functions and had antinociceptive effects in rodents. In silico targeting of the SUMOylation site in CRMP2 (Lys374) identified >200 hits, of which compound 194 exhibited selective in vitro and ex vivo NaV1.7 engagement. Orally administered 194 was not only antinociceptive in preclinical models of acute and chronic pain but also demonstrated synergy alongside other analgesics—without eliciting addiction, rewarding properties, or neurotoxicity. Analgesia conferred by 194 was opioid receptor dependent. Our results demonstrate that 194 is a first-in-class protein-protein inhibitor that capitalizes on CRMP2-NaV1.7 regulation to deliver safe analgesia in rodents.
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U2 - 10.1126/scitranslmed.abh1314
DO - 10.1126/scitranslmed.abh1314
M3 - Article
C2 - 34757807
AN - SCOPUS:85121742057
SN - 1946-6234
VL - 13
JO - Science translational medicine
JF - Science translational medicine
IS - 619
M1 - eabh1314
ER -