Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor

作者：Zining Wu, Todd L. Graybill, Xin Zeng, Michael Platchek, Jean Zhang, Vera Q. Bodmer, David D. Wisnoski, Jianghe Deng, Frank T. Coppo, Gang Yao, Alex M. Tamburino, Genaro S. Scavello, G. Joseph Franklin, Sibongile Mataruse, Katie L. Bedard, Yun Ding, Jing Chai, Jennifer D. Summerfield, Paolo A. Centrella, Jeffrey A. Messer, Andrew J. Pope, David I. Israel · 发表于：ACS Combinatorial Science · 年份：2015 · DOI：10.1021/acscombsci.5b00124 · 被引用次数：137 · 研究领域：Receptor Mechanisms and Signaling、Neuropeptides and Animal Physiology、Chemical Synthesis and Analysis

DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.