Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 11, Issue 519, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aaw8434
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Funding
- National Science and Technology Major Project Key New Drug Creation and Manufacturing Program of China [2018ZX09711002]
- National Natural Science Foundation of China [21422208, 31600832]
- Thousand Talents Plan in Sichuan Province
- 1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University [ZY2016101]
- ECNU [44300-19311-542500/006]
- Fundamental Research Funds for the Central Universities [2018SCUH0086]
- Special Program for Applied Research on Super Computation of the NSFC-Guangdong Joint Fund [U1501501]
- State Key Laboratory of Bioorganic and Natural Products Chemistry
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The paucity of selective agonists for TWIK-related acid-sensitive K+ 3 (TASK-3) channel, a member of two-pore domain K+ (K2P) channels, has contributed to our limited understanding of its biological functions. By targeting a druggable transmembrane cavity using a structure-based drug design approach, we discovered a biguanide compound, CHET3, as a highly selective allosteric activator for TASK-3-containing K2P channels, including TASK-3 homomers and TASK-3/TASK-1 heteromers. CHET3 displayed potent analgesic effects in vivo in a variety of acute and chronic pain models in rodents that could be abolished pharmacologically or by genetic ablation of TASK-3. We further found that TASK-3-containing channels anatomically define a unique population of small-sized, transient receptor potential cation channel subfamily M member 8 (TRPM8)-, transient receptor potential cation channel subfamily V member 1 (TRPV1)-, or tyrosine hydroxylase (TH)-positive nociceptive sensory neurons and functionally regulate their membrane excitability, supporting CHET3 analgesic effects in thermal hyperalgesia and mechanical allodynia under chronic pain. Overall, our proof-of-concept study reveals TASK-3-containing K2P channels as a druggable target for treating pain.
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