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.

Automated summary

This study reports a solid-phase synthesis method for constructing a DNA-encoded library of thioether-linked macrocycles. The library is designed to be highly diverse and minimize the number of amide N-H bonds to enhance cell permeability. The results demonstrate the utility of this library as a source of protein ligands, with the successful isolation of compounds that bind the model target, Streptavidin, with high affinity.