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4.3 Selections of DNA-Encoded Libraries to Protein Targets on Living Cells

DOI: 10.1055/sos-SD-241-00249

Cai, B.; Krusemark, C. J.Science of Synthesis: DNA-Encoded Libraries, (20241599.

General Introduction

Membrane proteins are essential regulators of various physiological processes and are the primary target class for approved small-molecule drugs.[‌1‌,‌2‌] While DNA-encoded library (DEL) technology has been transformative for small-molecule drug discovery, its utility in discovering ligands to integral membrane proteins is underexplored due to the inherent challenges with handling purified membrane proteins. Prior research has applied DEL selections to membrane proteins immobilized on solid supports.[‌3‌,‌4‌] The first demonstration of DEL selection to a membrane-protein target on live cells was reported by Israel and co-workers.[‌5‌] This approach relied upon obtaining high expression levels of a G-protein coupled receptor (GPCR), using the BacMam expression system, and enrichment of DNA-linked ligands using repeated cell washing and centrifugation. More recently, Neri and co-workers similarly applied a bivalent display DEL approach to a carbonic anhydrase IX target expressed on tumor cell surfaces.[‌6‌] Also, the Li group reported an approach that uses DNA-programmed affinity labelling (DPAL) to install a DNA tag on target proteins (see Section 4.2), which increases the binding affinity of DEL–ligand constructs through avidity and enables target-specific DEL selections against endogenous membrane proteins.[‌7‌]

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