Bo Cai; Dongwook Kim; Saeed Akhand; Yixing Sun; Robert Cassell; Aktan Alpsoy; Emily C. Dykhuizen; Richard M. van Rijn; Michael K. Wendt; Casey J. Krusemark
J. Am. Chem. Soc., 2019, 141, 43, 17057-17061
https://doi.org/10.1021/jacs.9b08085

Abstract

We report the selection of DNA-encoded small molecule libraries against protein targets within the cytosol and on the surface of live cells. The approach relies on generation of a covalent linkage of the DNA to protein targets by affinity labeling. This crosslinking event enables subsequent co-purification by a tag on the recombinant protein. To access targets within cells, a cyclic cell-penetrating peptide is appended to DNA-encoded libraries for delivery across the cell membrane. As this approach assesses binding of DELs to targets in live cells, it provides a strategy for selection of DELs against challenging targets that cannot be expressed and purified as active.