Chapter 4: Assays of DNA-encoded Libraries Against Protein Targets on and Within Living Cells

Assay platforms available for DNA-encoded chemical libraries (DELs) are largely limited to an in vitro selection assay for binding to a biochemical pure protein on a solid support. Extending DEL assays to proteins on the cell surface and within live cells offers the ability to assay targets that cannot be reconstituted biochemically and to assay targets in a more physiologically relevant state. Significant challenges exist that hinder the cellular application of DELs. In this review, we summarise the various approaches that have been applied to date that enable DEL assays against protein targets both on the cell surface and within live cells. We discuss the benefits and limitations of these approaches and how they address the unique challenges of live cell DEL assays. We explore the potential for molecular discovery from libraries of varying complexity. We highlight some of the molecules discovered successfully with live cell DEL assays and lastly offer an outlook for the future.