Synthesis and Selection of DNA-encoded Chemical Libraries

Abstract

Originally in 1992, Brenner and Lerner proposed the concept of using DNA as tags to encode chemical reactions in combinatorial library synthesis. During the past two decades, a variety of strategies of DNA-encoded libraries (DEL) have been developed. Benefiting from the high encoding capacity of DNA molecules, today’s DELs can be pre-pared with an extremely large number of compounds. Selections of DELs against biological targets can be accomplished using highly sensitive PCR amplification and ultra-high-throughput DNA sequencing technology. Selections of DELs have already generated many novel ligands against biological targets and have become a new discovery modality for researchers in both academia and pharmaceutical industry. Here we report our recent progresses on the strategies for the synthesis and selection of DNA-encoded libraries. Notably, we developed a “universal template” method able to prepare the entire library with a single DNA template; our novel selection method also enables the selection of DELs against previously intractable drug targets. These methods are being implemented in a variety of drug discovery programs.