DNA-encoded chemical libraries (DELs) represent a versatile and powerful technology platform for the discovery of small-molecule ligands to protein targets of biological and pharmaceutical interest. DELs are collections of molecules, individually coupled to distinctive DNA tags serving as amplifiable identification barcodes. Thanks to advances in DNA-compatible reactions, selection methodologies, next-generation sequencing, and data analysis, DEL technology allows the construction and screening of libraries of unprecedented size, which has led to the discovery of highly potent ligands, some of which have progressed to clinical trials. In this Review, we present an overview of diverse approaches for the generation and screening of DEL molecular repertoires. Recent success stories are described, detailing how novel ligands were isolated from DEL screening campaigns and were further optimized by medicinal chemistry. The goal of the Review is to capture some of the most recent developments in the field, while also elaborating on future challenges to further improve DEL technology as a therapeutic discovery platform.
DEL technology uses a specific DNA sequence to label each small molecule compound in the reaction process, and uses combinatorial chemistry principles to combine a large number of compounds with millions to billions of DNA sequences. Then, DEL is directly mixed with the target protein for affinity screening, and the unbound compounds are eluted to get a collection of compounds that can bind to the target protein. The DNA sequences of these compounds were amplified by PCR and detected by gene sequencing. Because there is a one-to-one correspondence between the DNA sequence and the small molecule compound, the researchers only need to read the DNA sequence on the compound to decode the structure of the corresponding compound.
The company uses a library of DNA-encoded compounds to help develop innovative drugs