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

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• 作者：Luca Mannocci ; Samu Melkko ; Fabian Buller ; Ilona Molnà ; r ; Jean-Paul Gapian Bianké ; Christoph E. Dumelin ; Jrg Scheuermann ; Dario Neri
• 刊名：Bioconjugate Chemistry
• 出版年：2010
• 出版时间：October 20, 2010
• 年：2010
• 卷：21
• 期：10
• 页码：1836-1841
• 全文大小：386K
• 年卷期：v.21,no.10(October 20, 2010)
• ISSN：1520-4812

文摘

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 >10000-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.