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A chemical approach for global protein knockdown from mice to non-human primates.
Cell Discovery ( IF 13.0 ) Pub Date : 2019-02-05 , 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
Cell Discovery ( IF 13.0 ) Pub Date : 2019-02-05 , 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
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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.
中文翻译：
从小鼠到非人类灵长类动物的整体蛋白敲除的化学方法。
尽管由于CRISPR / Cas9的使用增加，用于蛋白质敲除的常规基因修饰方法非常成功，但仍缺乏有效的技术来实现成年动物，特别是大型动物（例如非人类灵长类动物）中蛋白质的消耗。在这里，我们报告一种基于PROTACs技术的化学方法，该方法可在全球范围内高效，快速地敲除FKBP12（12 kDa FK506结合蛋白）蛋白。腹膜内和口服均可导致小鼠中FKBP12快速，稳定和可逆降解。该方法的效率和实用性已在大型和小型动物（小鼠，大鼠，巴马猪和恒河猴）中得到了成功证明。此外，我们证明了这种方法还可以有效地敲低其他目标蛋白，例如Bruton的酪氨酸激酶（BTK）。
更新日期：2019-11-18
中文翻译：
从小鼠到非人类灵长类动物的整体蛋白敲除的化学方法。
尽管由于CRISPR / Cas9的使用增加，用于蛋白质敲除的常规基因修饰方法非常成功，但仍缺乏有效的技术来实现成年动物，特别是大型动物（例如非人类灵长类动物）中蛋白质的消耗。在这里，我们报告一种基于PROTACs技术的化学方法，该方法可在全球范围内高效，快速地敲除FKBP12（12 kDa FK506结合蛋白）蛋白。腹膜内和口服均可导致小鼠中FKBP12快速，稳定和可逆降解。该方法的效率和实用性已在大型和小型动物（小鼠，大鼠，巴马猪和恒河猴）中得到了成功证明。此外，我们证明了这种方法还可以有效地敲低其他目标蛋白，例如Bruton的酪氨酸激酶（BTK）。
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