期刊
NATURE CHEMICAL BIOLOGY
卷 16, 期 3, 页码 318-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41589-020-0467-3
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资金
- National Institutes of Health (NIH) [R35 GM128618, R35 CA220340, R01 CA222218]
- Innovation Award from the Center for Microbiome Informatics and Therapeutics at MIT
- Harvard Digestive Diseases Center (NIH grant) [5P30DK034854-32]
- Karin Grunebaum Cancer Research Foundation Faculty Research Fellowship
- John and Virginia Kaneb Fellowship
- Quadrangle Fund for the Advancement and Seeding of Translational Research at Harvard Medical School (Q-FASTR) grant
- HMS Dean's Innovation Grant in the Basic and Social Sciences
- Wellington Postdoctoral Fellowship
- American Heart Association Postdoctoral Fellowship
- NSF Graduate Research Fellowship [DGE1745303]
- Swiss National Science Foundation
Bile salt hydrolase (BSH) enzymes are widely expressed by human gut bacteria and catalyze the gateway reaction leading to secondary bile acid formation. Bile acids regulate key metabolic and immune processes by binding to host receptors. There is an unmet need for a potent tool to inhibit BSHs across all gut bacteria to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSHs. From a rationally designed candidate library, we identified a lead compound bearing an alpha-fluoromethyl ketone warhead that modifies BSH at the catalytic cysteine residue. This inhibitor abolished BSH activity in conventional mouse feces. Mice gavaged with a single dose of this compound displayed decreased BSH activity and decreased deconjugated bile acid levels in feces. Our studies demonstrate the potential of a covalent BSH inhibitor to modulate bile acid composition in vivo. A covalent pan-inhibitor of bacterial bile salt hydrolases developed by adding a chenodeoxycholic acid moiety to the warhead is not bactericidal and is therefore useful for studying the effects of bile acids on host physiology.
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