Xie Jia, Wang Shuyue, Ma Peixiang, Ma Fei, Li Jie, Wang Wei, Lu Fengping, Xiong Huan, Gu Yuang, Zhang Shuning, Xu Hongtao, Yang Guang, Lerner Richard A
Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China; Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China.
iScience. 2020 Jun 26;23(6):101197. doi: 10.1016/j.isci.2020.101197. Epub 2020 May 23.
Although insulin is a life-saving medicine, administration by daily injection remains problematic. Our goal was to exploit the power of DNA-encoded libraries to identify molecules with insulin-like activity but with the potential to be developed as oral drugs. Our strategy involved using a 10-member DNA-encoded library containing 160 Traditional Chinese Medicines (nDEL) to identify molecules that bind to and activate the insulin receptor. Importantly, we used the natural ligand, insulin, to liberate bound molecules. Using this selection method on our relatively small, but highly diverse, nDEL yielded a molecule capable of both binding to and activating the insulin receptor. Chemical analysis showed this molecule to be a polycyclic analog of the guanidine metformin, a known drug used to treat diabetes. By using our protocol with other, even larger, DELs we can expect to identify additional organic molecules capable of binding to and activating the insulin receptor.
尽管胰岛素是一种救命药物，但每日注射给药仍然存在问题。我们的目标是利用DNA编码文库的力量来鉴定具有胰岛素样活性但有潜力开发为口服药物的分子。我们的策略包括使用一个包含160种中药的10元DNA编码文库（nDEL）来鉴定与胰岛素受体结合并激活它的分子。重要的是，我们使用天然配体胰岛素来释放结合的分子。在我们相对较小但高度多样化的nDEL上使用这种筛选方法，得到了一种既能与胰岛素受体结合又能激活它的分子。化学分析表明，该分子是用于治疗糖尿病的已知药物胍乙双胍的多环类似物。通过将我们的方案应用于其他甚至更大的DEL，我们有望鉴定出更多能够与胰岛素受体结合并激活它的有机分子。
