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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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Details
1 Tsinghua University, Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua-Peking Center for Life Sciences, Beijing, China (GRID:grid.12527.33)
2 Chinese Academy of Sciences, Institute of Biophysics, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309); University of the Chinese Academy of Sciences, Beijing, China (GRID:grid.410726.6) (ISNI:0000 0004 1797 8419)
3 Tsinghua University, Ministry of Education (MOE) Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178); Tsinghua University, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Beijing Advanced Innovation Center for Structural Biology, Beijing, China (GRID:grid.12527.33) (ISNI:0000 0001 0662 3178)
4 Peking University, Institute of Molecular Medicine, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319); Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319)
5 Chinese Academy of Sciences, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)
6 Peking University, State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319); Peking-Tsinghua Center for Life Sciences, Beijing, China (GRID:grid.452723.5)
7 Chinese Academy of Sciences, Institute of Biophysics, Beijing, China (GRID:grid.9227.e) (ISNI:0000000119573309)