Next Generation Cyclic Peptidomimetics: Novel Triazole Chemistry to Manufacture Multifunctional Cyclisation Moieties

Peptide macrocyclisation is a powerful strategy to constrain conformation and enhance the physicochemical properties of peptides. As peptide therapeutics continue to gain prominence, there is a growing need for stable, multifunctional cyclisation chemistries to support next-generation macrocyclic peptidomimetics. Here, we report an on-resin method to generate a multifunctional 5-iodo-triazole as a redox-stable disulfide bridge mimetic. Through the incorporation of two readily available commercial reagents, this cyclisation proceeds under mild conditions with high efficiency. The 5-iodo-triazole 4 enables late-stage diversification via Suzuki-Miyaura cross-coupling, and we establish optimised on-resin conditions compatible with a range of boronic esters. The resulting amine-functionalised analogue 12 was further derivatised to produce a versatile chemical biology toolbox. Notably, NMR analysis reveals that the 5-iodo-triazole 4 acts as a conformational constraint in proline-containing peptides, underscoring its utility in peptide design and discovery. This work provides a broadly applicable and modular platform for late-stage functional diversification of macrocyclic peptides, advancing the development of next-generation peptide-based therapeutics.