Homolysis of Alkoxyamines Triggered by Carbohydrate-Active Enzyme: A Step toward a General Platform to Generate Toxic...

The rise of drug-resistant pathogens and the dose-limiting side effects of current therapies highlight the urgent need for innovative treatment strategies. We recently demonstrated that hybrid alkoxyamine-peptide conjugates, upon enzymatic cleavage by specific peptidases, undergo C-O bond homolysis to generate highly reactive radical species capable of inducing broad-spectrum damage to pathogenic organisms (cancerous cells, parasites, fungi, etc.). Relying on this concept, we now report on the design and synthesis of a new class of enzyme-triggered, releasing radical prodrugs with a carbohydrate structure as a leaving group. These molecules offer a versatile strategy for the development of next-generation therapeutics that couple enzymatic specificity using glucosidase with controlled radical release to fight resistant and difficult-to-treat infections.