Photochemical Radical Thiol-yne Reaction Macrocyclizes Peptides, Yielding Potent, Redox-Stable Vinyl Sulfide Oxytocin Analog

Peptide therapeutics often face challenges with stability, cell permeability, and bioavailability due to their linear structure and susceptibility to enzymatic degradation. Peptide macrocyclization is a well-established strategy to overcome these limitations by rigidifying the peptide backbone, which can enhance target binding affinity, improve metabolic stability, and facilitate membrane penetration. Current cyclization methods can be harsh or limited in scope. There's a significant need for robust, mild, and versatile synthetic methodologies that can create stable bioisosteres, particularly for disulfide-containing peptides like many neuropeptides, which are prone to reduction and scrambling in biological environments.

Researchers developed a novel radical-mediated thiol-yne process for peptide macrocyclization. This methodology involves reacting a thiol-containing peptide with an alkyne under specific conditions to form vinyl sulfide products. The cyclization was achieved using mild conditions, specifically UV-A or blue LED irradiation, and was demonstrated to be effective in both organic and aqueous solvents. The team applied this method to synthesize a novel vinyl sulfide analogue of oxytocin, a biologically relevant neuropeptide. Furthermore, the adaptability of the method for late-stage modification of cyclic peptides using maleimide tags was also described, highlighting its broad utility for diverse peptide engineering applications.

The developed radical-mediated thiol-yne reaction successfully enabled the formation of cyclic peptides, generating vinyl sulfide products. This robust methodology operates under mild conditions, utilizing either UV-A or blue LED irradiation, and is compatible with both organic and aqueous solvents, offering significant versatility for various synthetic contexts. A key finding was the successful creation of a disulfide bioisostere to a range of biologically relevant neuropeptides. Specifically, the synthesis of a novel vinyl sulfide analogue of oxytocin demonstrated significant improvements over the parent compound. This analog exhibited both enhanced potency and redox stability, critical attributes for therapeutic development. The ability to adapt this methodology for late-stage modification using maleimide tags further underscores its utility for complex peptide architectures and bioconjugation strategies. This provides a new, efficient route to stable peptide mimetics.