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

详细信息    查看全文

• 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 Tamburino ; Genaro Scavello ; G. Joseph Franklin ; Sibongile Mataruse ; Katie L. Bedard ; Yun Ding ; Jing Chai ; Jennifer Summerfield ; Paolo A. Centrella ; Jeffrey A. Messer ; Andrew J. Pope ; David I. Israel
• 刊名：ACS Combinatorial Science
• 出版年：2015
• 出版时间：December 14, 2015
• 年：2015
• 卷：17
• 期：12
• 页码：722-731
• 全文大小：508K
• ISSN：2156-8944

文摘

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.