DNA-encoded chemical libraries of macrocycles

•Generation of macrocyclic libraries using DNA-encoded chemistry.•Modulating protein–protein interactions.•Library design based on known peptide binder.•Empirical screening approach identifies family of library hits.•Low nanomolar binders identified directly from library screen.Conformationally constrained macrocyclic molecules can present functionally diverse chemical groups distributed over a relatively large molecular surface. This class of molecule is well suited to bind to the extended interface surfaces typical of protein–protein interactions that make up key therapeutically relevant pathways. Large numbers of macrocycles can be generated using DNA-encoded technologies to yield chemically diverse libraries where individual macrocycles are identifiable by a unique covalently attached DNA sequence. Recent developments in this field have revealed library-generated macrocycles possessing potent affinity against tough targets such as XIAP, IL17 and IDE. This review highlights recent progression toward developing drug-like macrocycles and as illustration, advances against these targets.