Chapter 7: DNA-encoded Library Technology (ELT)

DNA-encoded library technology (ELT) is being increasingly utilized for small-molecule lead discovery. ELT involves the synthesis and screening of DNA-encoded libraries (DELs) and the decoding of DEL binders. DELs are composed of chimeric compounds that consist of a small molecule covalently linked to a single-stranded (ss) or double-stranded (ds) DNA whose sequence uniquely encodes the identity of the small molecule. DELs with sizes of up to 10¹² novel encoded small molecules can be screened as a pool by affinity selection due to the PCR-amplifiable DNA-tag. The decoding of the binders is typically achieved by amplification and sequencing of the associated DNA-tags, which has been greatly facilitated by advances and access to next-generation sequencing. Screening of DELs has yielded a large number of bioactive molecules with drug-like properties that have been developed into high-quality chemical biology probes and even clinical candidates. This chapter describes the synthesis, screening and practical applications of DELs for the identification of novel small-molecule leads for drug discovery and chemical biology probes.