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

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.