Jia Xie; Shuyue Wang; Peixiang Ma; Fei Ma; Jie Li; Wei Wang; Fengping Lu; Huan Xiong; Yuang Gu; Shuning Zhang; Hongtao Xu; Guang Yang; Richard A. Lerner
iScience, 2020, 23(6), 101197
https://doi.org/10.1016/j.isci.2020.101197

Abstract

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 104 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.