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However, currently available inhibitors are predominantly reversible and nonselective, leading to incomplete target engagement, concomitant \u03b1\u2010amylase inhibition, and gastrointestinal side effects associated with gut microbiota perturbation. Here, we report a SuFEx\u2010enabled reprogramming strategy that converts natural flavonoids into highly selective \u03b1\u2010glucosidase covalent inhibitors. Guided by the structure of human intestinal maltase\u2013glucoamylase, fluorosulfate warheads were introduced via Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry, yielding covalently active derivatives with markedly enhanced affinity and selectivity toward \u03b1\u2010glucosidase over \u03b1\u2010amylase. The lead compound FS6\u20102 forms an active\u2010site\u2010directed covalent interaction with a conserved lysine residue, resulting in sustained inhibition of starch digestion in vitro and in vivo. In diabetic mice, SuFEx\u2010modified flavonoids improved glycemic control, preserved pancreatic integrity, and remodeled gut microbiota composition, restoring microbial diversity and metabolic function. This work validates SuFEx\u2010enabled covalent reprogramming as a powerful strategy to transform dietary natural products into precision metabolic medicines, offering a versatile platform for developing selective, microbiota\u2010compatible metabolic therapeutics.<\/jats:p>","DOI":"10.1002\/advs.75869","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T14:10:16Z","timestamp":1780063816000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SuFEx\u2010Enabled Reprogramming of Flavonoids for Selective \u03b1\u2010Glucosidase Covalent Inhibition"],"prefix":"10.1002","volume":"13","author":[{"given":"Fengyu","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-4396-0966","authenticated-orcid":false,"given":"Liwei","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minlong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjin","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Health China Agricultural University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangzhou Women and Children's Medical Center GMU\u2010GIBH Joint School of Life Sciences Guangzhou Medical University  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Chen","sequence":"additional","affiliation":[{"name":"National Key Laboratory of Immunity and Inflammation Suzhou Institute of Systems Medicine Institution Chinese Academy of Medical Science &amp; 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