2. Academic Validation
  3. SoNar, a Highly Responsive NAD+/NADH Sensor, Allows High-Throughput Metabolic Screening of Anti-tumor Agents

SoNar, a Highly Responsive NAD+/NADH Sensor, Allows High-Throughput Metabolic Screening of Anti-tumor Agents

  • Cell Metab. 2015 May 5;21(5):777-89. doi: 10.1016/j.cmet.2015.04.009.
Yuzheng Zhao 1,  Qingxun Hu 2,  Feixiong Cheng 3,  Ni Su 4,  Aoxue Wang 4,  Yejun Zou 4,  Hanyang Hu 2,  Xianjun Chen 4,  Hai-Meng Zhou 5,  Xinzhi Huang 6,  Kai Yang 6,  Qian Zhu 7,  Xue Wang 2,  Jing Yi 6,  Linyong Zhu 8,  Xuhong Qian 9,  Lixin Chen 10,  Yun Tang 3,  Joseph Loscalzo 11,  Yi Yang 12
Affiliations

Affiliations

  • 1 Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Collaborative Innovation Center of Genetics and Development, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 2 Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 3 Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 4 Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 5 Zhejiang Provincial Key Laboratory of Applied Enzymology, Yangtze Delta Region Institute of Tsinghua University, Jiaxing 314006, China.
  • 6 Department of Biochemistry and Molecular Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, 280 S. Chongqing Road, Shanghai 200025, China.
  • 7 Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 8 Key Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 9 Shanghai Key Laboratory of Chemical Biology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China.
  • 10 Shanghai Laboratory Animal Center, Chinese Academy of Sciences, Shanghai 201615, China.
  • 11 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 12 Synthetic Biology and Biotechnology Laboratory, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Optogenetics & Molecular Imaging Interdisciplinary Research Center, CAS Center for Excellence in Brain Science, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Collaborative Innovation Center of Genetics and Development, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China; Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China. Electronic address: [email protected].
PMID: 25955212 DOI: 10.1016/j.cmet.2015.04.009
Abstract

The altered metabolism of tumor cells confers a selective advantage for survival and proliferation, and studies have shown that targeting such metabolic shifts may be a useful therapeutic strategy. We developed an intensely fluorescent, rapidly responsive, pH-resistant, genetically encoded sensor of wide dynamic range, denoted SoNar, for tracking cytosolic NAD(+) and NADH redox states in living cells and in vivo. SoNar responds to subtle perturbations of various pathways of energy metabolism in real time, and allowed high-throughput screening for new agents targeting tumor metabolism. Among > 5,500 unique compounds, we identified KP372-1 as a potent NQO1-mediated redox cycling agent that produced extreme oxidative stress, selectively induced Cancer cell Apoptosis, and effectively decreased tumor growth in vivo. This study demonstrates that genetically encoded sensor-based metabolic screening could serve as a valuable approach for drug discovery.

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