SuFEx‐Enabled Reprogramming of Flavonoids for Selective α‐Glucosidase Covalent Inhibition

ABSTRACT Selective inhibition of intestinal α‐glucosidase is an established strategy for controlling postprandial hyperglycemia. However, currently available inhibitors are predominantly reversible and nonselective, leading to incomplete target engagement, concomitant α‐amylase inhibition, and gastrointestinal side effects associated with gut microbiota perturbation. Here, we report a SuFEx‐enabled reprogramming strategy that converts natural flavonoids into highly selective α‐glucosidase covalent inhibitors. Guided by the structure of human intestinal maltase–glucoamylase, fluorosulfate warheads were introduced via Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry, yielding covalently active derivatives with markedly enhanced affinity and selectivity toward α‐glucosidase over α‐amylase. The lead compound FS6‐2 forms an active‐site‐directed covalent interaction with a conserved lysine residue, resulting in sustained inhibition of starch digestion in vitro and in vivo. In diabetic mice, SuFEx‐modified flavonoids improved glycemic control, preserved pancreatic integrity, and remodeled gut microbiota composition, restoring microbial diversity and metabolic function. This work validates SuFEx‐enabled covalent reprogramming as a powerful strategy to transform dietary natural products into precision metabolic medicines, offering a versatile platform for developing selective, microbiota‐compatible metabolic therapeutics.