2. Academic Validation
  3. Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents

Selective targeting of NaV1.7 via inhibition of the CRMP2-Ubc9 interaction reduces pain in rodents

  • Sci Transl Med. 2021 Nov 10;13(619):eabh1314. doi: 10.1126/scitranslmed.abh1314.
Song Cai 1,  Aubin Moutal 1,  Jie Yu 1,  Lindsey A Chew 1,  Jörg Isensee 2,  Reena Chawla 3,  Kimberly Gomez 1,  Shizhen Luo 1,  Yuan Zhou 1,  Aude Chefdeville 1,  Cynthia Madura 1,  Samantha Perez-Miller 1 4,  Shreya Sai Bellampalli 1,  Angie Dorame 1,  David D Scott 1,  Liberty François-Moutal 1,  Zhiming Shan 1,  Taylor Woodward 5,  Vijay Gokhale 3 6,  Andrea G Hohmann 5,  Todd W Vanderah 1 7,  Marcel Patek 8 9,  May Khanna 1 3 4 8,  Tim Hucho 2,  Rajesh Khanna 1 3 4 7 8
Affiliations

Affiliations

  • 1 Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
  • 2 Department of Anesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital of Cologne, University Cologne, Joseph-Stelzmann-Str 9, Cologne D-50931, Germany.
  • 3 BIO5 Institute, 1657 East Helen Street, Tucson, AZ 85721, USA.
  • 4 Center for Innovation in Brain Sciences, University of Arizona, Tucson, AZ 85721, USA.
  • 5 Department of Psychological and Brain Sciences, Program in Neuroscience and Gill Center for Biomolecular Science, Indiana University, Bloomington, IN 47405-2204, USA.
  • 6 College of Pharmacy, University of Arizona, 1703 East Mabel Street, Tucson, AZ 85721, USA.
  • 7 Comprehensive Pain and Addiction Center, The University of Arizona, Tucson, AZ 85724, USA.
  • 8 Regulonix LLC, 1555 E. Entrada Segunda, Tucson, AZ 85718, USA.
  • 9 Bright Rock Path LLC, Tucson, AZ 85724, USA.
PMID: 34757807 DOI: 10.1126/scitranslmed.abh1314
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.

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