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4.4 Selections of DNA-Encoded Libraries to Protein Targets within Living Cells

DOI: 10.1055/sos-SD-241-00252

Cai, B.; Krusemark, C. J.Science of Synthesis: DNA-Encoded Libraries, (20241607.

General Introduction

While DNA-encoded libraries (DELs) now play an important role in drug discovery, selections of DELs have been largely limited to biochemically pure proteins that are immobilized on solid supports. As the concentration of active protein is the driver for ligand binding, high protein purity and activity are critical parameters in DEL selections. Unfortunately, many sought-after drug targets cannot be purified or reconstituted biochemically, which excludes them from the traditional DEL approach.[‌1‌] Additionally, even in best-case scenarios, significant time and effort in a DEL campaign is devoted to protein production and quality control. Performing DEL selections against protein targets within live cells would be desirable and remove the requirement of prior protein purification.[‌2‌,‌3‌] This would allow assessment of ligand binding to target proteins within a more native environment, where post-translational modifications and endogenous binding partners can be preserved.[‌4‌] Furthermore, selections against intracellular proteins, rather than stand-alone protein targets, may be more likely to generate effective lead compounds that retain activity in vivo.[‌5‌]

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