Modular assembly and encoding strategies for dual-display DNA-encoded chemical libraries

DNA-encoded chemical libraries (DELs) are increasingly being used for the discovery of protein ligands and can be constructed displaying either one or two molecules at the extremities of the two complementary DNA strands. Here, we describe that DELs, featuring the simultaneous display of two molecules, can be encoded using various types of DNA structures, which go beyond the use of conventional double-stranded DNA fragments. Specifically, we compared dual-display methodologies in hairpin, circular or linear formats in terms of polymerase chain reaction (PCR) amplifiability and performance in affinity capture selections. The methods reported in this article highlight the feasibility and modularity of the described encoding strategies and may thus further expand the scope of DNA-encoded chemistry, particularly for the identification of compounds which recognize adjacent epitopes on the surface of target proteins of interest.