Selecting DNA-encoded Chemical Library Against Nonimmobilized Proteins Using a “Ligate-Crosslink-Purify” Strategy

Abstract

DNA-encoded chemical library (DEL) has recently emerged and become an important technology platform in biomedical research and drug discovery. DELs containing large numbers of compounds can be prepared and selected against biological targets to discover novel ligands and inhibitors. In practice, DELs are usually selected against purified and immobilized proteins using the typical “bind-wash-elute” protocol; however, selection methods compatible with non-immobilized proteins would be able to greatly expand the target scope of DELs beyond purified proteins to more complex and biologically relevant targets. Using a novel “ligate-crosslink-purify” strategy, here we report a method capable of selecting DELs against unmodified and non-immobilized protein targets. In addition, this method has shown excel-lent capability in identify binders with moderate and weak affinities.