2. Academic Validation
  3. A chemical approach for global protein knockdown from mice to non-human primates

A chemical approach for global protein knockdown from mice to non-human primates

  • Cell Discov. 2019 Feb 5;5:10. doi: 10.1038/s41421-018-0079-1.
Xiuyun Sun  # 1 2 3,  Jun Wang  # 4 5,  Xia Yao  # 1 2,  Wen Zheng 6 7,  Yang Mao 4 5,  Tianlong Lan 1 2,  Liguo Wang 1 2,  Yonghui Sun 1 2,  Xinyi Zhang 4 5,  Qiuye Zhao 1 2,  Jianguo Zhao 8,  Rui-Ping Xiao 9 10,  Xiuqin Zhang 6 7,  Guangju Ji 4,  Yu Rao 1 2
Affiliations

Affiliations

  • 1 1Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084 China.
  • 2 2MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua University, Beijing, 100084 China.
  • 3 Tsinghua-Peking Center for Life Sciences, Haidian District, Beijing, 100084 China.
  • 4 4Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101 China.
  • 5 5University of the Chinese Academy of Sciences, Beijing, 100049 China.
  • 6 6Institute of Molecular Medicine, Peking University, Beijing, 100871 China.
  • 7 7Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871 China.
  • 8 8State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101 China.
  • 9 9State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing, 100871 China.
  • 10 10Peking-Tsinghua Center for Life Sciences, Beijing, 100871 China.
  • # Contributed equally.
PMID: 30729032 DOI: 10.1038/s41421-018-0079-1
Abstract

Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult Animals, especially in large Animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small Animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (Btk). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in Animals, particularly in large Animals, for which gene-targeted knockout strategies may remain unfeasible.

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