Cai, Song, Moutal, Aubin ORCID: 0000-0003-4268-1206, Yu, Jie ORCID: 0000-0002-6768-7236, Chew, Lindsey A., Isensee, Jorg, Chawla, Reena, Gomez, Kimberly ORCID: 0000-0003-1867-5041, Luo, Shizhen, Zhou, Yuan, Chefdeville, Aude, Madura, Cynthia, Perez-Miller, Samantha ORCID: 0000-0002-9034-3693, Bellampalli, Shreya Sai, Dorame, Angie, Scott, David D., Francois-Moutal, Liberty, Shan, Zhiming ORCID: 0000-0002-4575-3933, Woodward, Taylor, Gokhale, Vijay, Hohmann, Andrea G., Vanderah, Todd W., Patek, Marcel, Khanna, May, Hucho, Tim and Khanna, Rajesh (2021). Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents. Sci. Transl. Med., 13 (619). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1946-6242

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Cai, SongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moutal, AubinUNSPECIFIEDorcid.org/0000-0003-4268-1206UNSPECIFIED
Yu, JieUNSPECIFIEDorcid.org/0000-0002-6768-7236UNSPECIFIED
Chew, Lindsey A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isensee, JorgUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chawla, ReenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gomez, KimberlyUNSPECIFIEDorcid.org/0000-0003-1867-5041UNSPECIFIED
Luo, ShizhenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhou, YuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chefdeville, AudeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Madura, CynthiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perez-Miller, SamanthaUNSPECIFIEDorcid.org/0000-0002-9034-3693UNSPECIFIED
Bellampalli, Shreya SaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorame, AngieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Scott, David D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Francois-Moutal, LibertyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Shan, ZhimingUNSPECIFIEDorcid.org/0000-0002-4575-3933UNSPECIFIED
Woodward, TaylorUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gokhale, VijayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohmann, Andrea G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanderah, Todd W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patek, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khanna, MayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khanna, RajeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-593811
DOI: 10.1126/scitranslmed.abh1314
Journal or Publication Title: Sci. Transl. Med.
Volume: 13
Number: 619
Date: 2021
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication: WASHINGTON
ISSN: 1946-6242
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RESPONSE MEDIATOR PROTEIN-2; GATED SODIUM-CHANNELS; OPIOID RECEPTORS; AGONIST BINDING; SENSORY NEURONS; DORSAL-ROOT; SUMOYLATION; EXPRESSION; NA(V)1.7; MECHANISMMultiple languages
Cell Biology; Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59381

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