Luca Mannocci; Samu Melkko; Fabian Buller; Ilona Molnàr; Jean-Paul Gapian Bianké; Christoph E. Dumelin; Jörg Scheuermann; Dario Neri
Bioconjugate Chem., 2010, 21, 10, 1836-1841
https://doi.org/10.1021/bc100198x

Abstract

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.