2. Academic Validation
  3. Optical control of the cardiac rhythm with photoswitchable NaV1.5 channel blockers

Optical control of the cardiac rhythm with photoswitchable NaV1.5 channel blockers

  • Nat Commun. 2026 Mar 10. doi: 10.1038/s41467-026-70305-6.
Shiqi Liu # 1 2,  Weiqiang Guan # 3,  Zhangqiang Li # 4,  Wei Wang # 1 2,  Huifang Song 1 2,  Jia'ao Li 4,  Junjie Hou 5,  Huan Wang 4,  JingWei Xiong 5,  Min Yang 6 7,  Nieng Yan 8 9,  Xin Tian 10 11,  Houhua Li 12,  Zhuo Huang 13 14
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural and Biomimetic Drugs and Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 IDG/McGovern Institute for Brain Research, Peking University, Beijing, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, China.
  • 4 Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
  • 5 School of Basic Medical Sciences, The Second Affiliated Hospital, Institute of Biomedical Innovation, The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Jiangxi Medical College, Nanchang University, Nanchang, China.
  • 6 Department of Geriatrics, Laboratory of Research and Translation for Geriatric Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 7 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing, China.
  • 8 Beijing Frontier Research Center for Biological Structures, State Key Laboratory of Membrane Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. nyan@tsinghua.edu.cn.
  • 9 Institute of Bio-Architecture and Bio-Interactions (IBABI), Shenzhen Medical Academy of Research and Translation, Guangming District, Shenzhen, Guangdong Province, China. nyan@tsinghua.edu.cn.
  • 10 Department of Geriatrics, Laboratory of Research and Translation for Geriatric Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China. xintian@cqmu.edu.cn.
  • 11 Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Major Neurological and Mental Disorders, Chongqing, China. xintian@cqmu.edu.cn.
  • 12 State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center, School of Pharmaceutical Sciences, Peking University, Beijing, China. lihouhua@pku.edu.cn.
  • 13 State Key Laboratory of Natural and Biomimetic Drugs and Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. huangz@hsc.pku.edu.cn.
  • 14 IDG/McGovern Institute for Brain Research, Peking University, Beijing, China. huangz@hsc.pku.edu.cn.
  • # Contributed equally.
PMID: 41807386 DOI: 10.1038/s41467-026-70305-6
Abstract

Voltage-gated Sodium Channel NaV1.5 is essential for cardiac excitability, mediating the rapid depolarization phase of the cardiac action potential (AP) and ensuring proper electrical conduction in the heart. Dysfunction of NaV1.5 is implicated in life-threatening arrhythmias, making it a critical therapeutic target. Acting as a NaV1.5 open-state blocker, quinidine demonstrates efficacy in arrhythmia treatment, but its low specificity restricts its clinical application. Here, we report an optopharmacological strategy that enables a precise and optical control of NaV1.5 function by means of photoswitchable quinidine derivatives. Through systematic structural optimization, we identify azo-Q2a as a high-performance photoswitchable inhibitor, exhibiting low activity in the dark or under 480 nm light irradiation (trans isomer), while approximately 7-fold higher efficacy is observed under 365 nm light irradiation (cis isomer). Of note, azo-Q2a demonstrates exceptional selectivity for NaV1.5 over cardiac ion channels and Other NaV1 subtypes, minimizing potential off-target effects. Furthermore, by solving the cryo-EM structure of the NaV1.5 in complex with the cis-active isomer azo-Q2a (3.0 Å resolution), we reveal the essential binding site that is responsible for the optical control of NaV1.5. Finally, azo-Q2a also attenuates the heart rate of living zebrafish larvae with light, showing its potential in cardiac-related research and treatment. Our work not only establishes azo-Q2a as a robust photoswitchable inhibitor for NaV1.5 but also provides a structural blueprint for the rational design of next-generation optopharmacological antiarrhythmic agents.

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