Cell

Enzyme

Biology

Gene

Genomic library

Artificial intelligence

Chemistry

Recombinant DNA

Computer science

Target protein

Computational biology

Cell biology

Cytosol

Base sequence

Biochemistry

Selection (genetic algorithm)

Journal of the American Chemical Society

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 cross-linking event enables subsequent copurification 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.

Selection of DNA-Encoded Libraries to Protein Targets within and on Living Cells