Macrocyclic peptide libraries built on DNA-encoded library, DEL, or display platforms depend on cyclization chemistries that are fast, aqueous, and biocompatible, yet existing methods carry persistent trade-offs. Thioether formation and copper-catalyzed azide-alkyne cycloaddition, CuAAC, are widely used, but both face linker instability, metal-induced DNA damage, and residual metal contamination that can require resource-intensive linker replacement. Metal-free chemistries that match the biocompatibility of those approaches while furnishing stable linkers are therefore highly desirable. A separate gap concerned the target class itself: whether macrocyclic peptides can efficiently bind the ATP-binding pocket of RIPK1 and inhibit its catalytic activity had remained underexplored.
Researchers on the Fan and Mi Teams at Merck & Co., Inc., published in the Journal of the American Chemical Society, turned to sulfur-fluoride exchange, SuFEx, chemistry to address both problems. Their strategy embeds a phenol and an aryl sulfonyl fluoride within a DNA-tagged peptide so that intramolecular cyclization triggers upon dissolution in basic aqueous buffer; tethering the SuFEx hub to an aryl alcohol raises effective molarity and suppresses competing hydrolysis. The team attributes the preference for aqueous conditions to hydrophobic preorganization of the aryl rings, though they note this explanation is their attribution rather than a directly proven mechanism. Applied to DEL synthesis, SuFEx cyclization supported a 343-million-member macrocyclic peptide library, and affinity selection against RIPK1 delivered what the authors describe as, to their knowledge, the first cyclic-peptide inhibitor of that kinase, with biochemical potency confirmed in an ADP-Glo kinase assay at an EC50 of 174 nM.
The authors describe SuFEx cyclization as a robust, DEL-compatible strategy for programmable macrocycle design and drug discovery, and propose it is expected to take its place alongside CuAAC and thioether formation for therapeutic macrocyclic peptide development. For peptide chemists working on kinase-targeted macrocycles or next-generation DEL platforms, the full building-block scope, selectivity data, conformational analysis, and screening workflow are detailed in the original publication.
