Work

Unified Access to Biaryl-Bridged Linkages Unlocks Structural Diversification of Noncanonical Cyclic Peptides

Year: 2026

Type: article

Abstract: Among ribosomally synthesized and post-translationally modified peptides (RiPPs), there exist distinctive cyclic peptides featuring rigid biaryl-bridged linkages. These biaryl-bridged cyclic peptides exhibit advantages not typically observed in conventional cyclic peptides, including (i) enhanced stability in biological systems, (ii) improved cell membrane permeability, (iii) selective binding to target proteins, and (iv) favorable oral bioavailability. However, the supply of such biaryl-bridged cyclic peptides has been constrained by their rigidity, which limits the applicability of common cyclization methods such as amide coupling and Ullmann coupling that are routinely employed in cyclic peptide synthesis. In this study, we report a systematic and comprehensive strategy for the incorporation of ten distinct biaryl/triaryl-bridged linkages—both natural and artificial types inspired by RiPPs—into arbitrary peptide linkers. This approach enables systematic access to RiPP derivatives from readily available building blocks. Furthermore, the methodology facilitates the preparation of fluorine-containing RiPPs, which play an important role in medicinal chemistry, as well as the synthesis of biaryl-bridged cyclic peptides with diverse ring sizes. In addition, more than forty analogs of the antibacterial RiPP cihunamide B were synthesized and evaluated, leading to the identification of several compounds with antibacterial activity surpassing that of the natural product.

Source: Journal of the American Chemical Society

DOI: 10.1021/jacs.6c05294