DNA-encoded chemical libraries (DELs) have been used for the discovery of novel macrocyclic peptides for protein targets of interest. We review the reported macrocyclic DELs and discuss the achievements and challenges of this promising field.

The synthesis and characterization of an ovel DNA-encodedl ibraryo fm acrocyclic peptided erivatives are described;t he macrocyclesa re based on three sets of proteinogenic and non-proteinogenic amino acid building blocks and featuring the use of copper(I)-catalyzeda lkyneazide cycloaddition (CuAAC) reactionf or ring closure. The library (termedY O-DEL) whichc ontains1254 838 compounds, was encoded with DNA in single-stranded format andw as screened against target proteins of interest using affinity capturep rocedures and photocrosslinking. YO-DEL selections yieldeds pecific binders against serum albumins, carbonic anhydrases and NKp46, am arker of activated Natural Killer cells.

Large Encoding Design (LED) allows for the construction of DNA-encoded chemical libraries (DELs) of unprecedented sizes and designs. LED was validated and compared with previous encoding systems for amplifiability and performance in test selections.

Modular assembly methodologies of DNA-encoded chemical libraries featuring dual-display of organic molecules.

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