Researchers developed a method to synthesize macrocyclic peptides by crosslinking two lysine amines using (thio)urea bridges, according to a study published in Nature Communications on September 2, 2026. The approach addresses a persistent challenge in drug development caused by the scarcity of efficient cyclization strategies for natural peptides.
The chemical process executes site-selective lysine-lysine crosslinking on native peptides by employing N, N’-carbonyldiimidazole or N, N’-thiocarbonyldiimidazole as bridging reagents. In addition, the scientists synthesized dual thiourea-bridged macrocyclic peptides through a one-pot, two-step multicomponent macrocyclization reaction. The strategies enable chemoselective macrocyclization even when peptides carry diverse nucleophilic residues.
The researchers demonstrated the technique by converting the targeted peptide RGD (Arg-Gly-Asp) and an antimicrobial Anoplin analogue into macrocyclic structures. Biological evaluations revealed that the resulting cyclopeptides, especially the thiourea- and bis-thiourea-bridged analogs, exhibited enhanced target binding affinity, potent antitumor activity, improved stability, and better membrane permeability.
Molecular docking simulations clarified the structural origin of the improved bioactivity. The docking work suggested that reinforced molecular interactions might serve as the underlying cause for the functional gains observed during biological evaluation.
The research involved investigators from Guangdong Medical University, the Dongguan University of Technology, and Nankai University. The work was supported by grants including the Guangdong Provincial Key Scientific Research Projects for Ordinary Higher Education Institutions and the Guangdong Medical Scientific Research Fund. The journal received the manuscript on November 26, 2025, and accepted it on August 20, 2026.
