Development of a covalent inhibitor of gut bacterial bile salt hydrolases.

Autor: Adhikari AA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Seegar TCM; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Ficarro SB; Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., McCurry MD; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Ramachandran D; Division of Endocrinology, Metabolism, and Diabetes, Beth Israel Deaconness Medical Center, Boston, MA, USA., Yao L; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Chaudhari SN; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Ndousse-Fetter S; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Banks AS; Division of Endocrinology, Metabolism, and Diabetes, Beth Israel Deaconness Medical Center, Boston, MA, USA., Marto JA; Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA., Blacklow SC; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA., Devlin AS; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA. sloan_devlin@hms.harvard.edu.
Jazyk: angličtina
Zdroj: Nature chemical biology [Nat Chem Biol] 2020 Mar; Vol. 16 (3), pp. 318-326. Date of Electronic Publication: 2020 Feb 10.
DOI: 10.1038/s41589-020-0467-3
Abstrakt: 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.
Databáze: MEDLINE
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