Isolation of Potent and Specific Trypsin Inhibitors from a DNA-Encoded Chemical Library

• Published in: Bioconjugate chemistry Vol. 21; no. 10; pp. 1836 - 1841
• Main Authors: Mannocci, Luca, Melkko, Samu, Buller, Fabian, Molnàr, Ilona, Gapian Bianké, Jean-Paul, Dumelin, Christoph E, Scheuermann, Jörg, Neri, Dario
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 20.10.2010
• Subjects: Base Sequence; Benzamidines - chemistry; Benzamidines - pharmacology; Chemical compounds; Chemical synthesis; Deoxyribonucleic acid; DNA; DNA - chemistry; DNA - genetics; Drug Evaluation, Preclinical - methods; Gene expression; Inhibitor drugs; Inhibitory Concentration 50; Molecular structure; Proteins; Small Molecule Libraries - chemistry; Small Molecule Libraries - pharmacology; Trypsin - metabolism; Trypsin Inhibitors - chemistry; Trypsin Inhibitors - pharmacology
• ISSN: 1043-1802; 1520-4812
• DOI: 10.1021/bc100198x

Collections of chemical compounds, individually attached to unique DNA fragments serving as amplifiable identification bar codes, are generally referred to as “DNA-encoded chemical libraries”. Such libraries can be used for the de novo isolation of binding molecules against target proteins of interest. Here, we describe the synthesis and use of a DNA-encoded library based on benzamidine analogues, which allowed the isolation of a trypsin inhibitor with an IC50 value of 3.0 nM, thus representing a >10 000-fold potency improvement compared to the parental compound. The novel trypsin inhibitor displayed an excellent selectivity toward other serine proteases. This study indicates that DNA-encoded libraries can be used for the facile “affinity maturation” of suboptimal binding compounds, thus facilitating drug development.