On-resin Synthesis and Late-Stage Functionalization of Macrocy-clic Peptidomimetics via 5-Iodo-1,4-Triazoles

We report an on-resin strategy for synthesizing 5-iodo-1,4-disubstituted-1,2,3-triazole-containing macrocyclic peptides as multifunctional disulfide bridge mimetics. Optimized CuAAC and Suzuki-Miyaura conditions enabled late-stage arylation at the triazole 5-position. This approach offers a novel strategy for fluorescent and biotin functionalization of peptides. Struc-tural analysis revealed that the 5-iodo substituent influences peptide conformation. These findings establish 5-iodo-1,4-triazoles as versatile, tunable motifs for macrocyclization and functionalization, expanding the chemical space accessible for macrocyclic peptide chemical biology tools and therapeutics.