Toward the Chemoenzymatic Synthesis of DNA-Encoded Libraries

DNA-encoded libraries (DELs) have become a powerful platform in drug discovery, practiced both by the pharmaceutical industry and academia. Each small molecule contained in a DEL is covalently linked to a DNA tag which serves as an amplifiable barcode facilitating binder identification. However, the chemical diversity accessible in DELs remains limited by the need to perform reactions under conditions that preserve the integrity of the DNA tag. Additionally, chemical reactions must proceed with high efficiency and selectivity to minimize side products and unreacted starting materials, which cannot be removed and may hamper hit identification. Consequently, expanding the DEL chemical space requires the development of methods that combine high reaction performance with DNA compatibility. In this outlook, we highlight the potential of enzymatic catalysis for on-DNA synthesis, which offers a promising route to expand DEL-accessible chemical space.