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

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.