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

• Published in: Angewandte Chemie 2022-04, Vol.134 (18), p.n/a
• Main Authors: Koesema, Eric, Roy, Animesh, Paciaroni, Nicholas G., Coito, Carlos, Tokmina‐Roszyk, Michal, Kodadek, Thomas
• Format: Article
• Language: English
• Subjects: Cell permeability; Chemistry; Combinatorial Chemistry; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA-Encoded Library; High-Throughput Screening; Libraries; Ligands; Macrocycles; Protein sources; Solid phase methods; Solid phase synthesis; Streptavidin
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202116999

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. The discovery of ligands for the “undruggable proteome” is likely to require the development of new chemical matter with a greater “molecular wingspan” than traditional Lipinski‐compliant small molecules. A DNA‐encoded library (DEL) of non‐peptidic thioether macrocycles has been constructed and screened for high affinity protein ligands to a model protein, SA.