Synthesis and Screening of a DNA‐Encoded Library of Non‐Peptidic Macrocycles

There is considerable interest in the development of libraries of non‐peptidic macrocycles as a source of ligands for difficult targets. We report here the solid‐phase synthesis of a DNA‐encoded library of several hundred thousand thioether‐linked macrocycles. The library was designed to be highly diverse with respect to backbone scaffold diversity and to minimize the number of amide N−H bonds, which compromise cell permeability. The utility of the library as a source of protein ligands is demonstrated through the isolation of compounds that bind Streptavidin, a model target, with high affinity.