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Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases

Arijit A. Adhikari, Tom C. Seegar, Scott B. Ficarro, Megan D. McCurry, Deepti Ramachandran, Lina Yao, Snehal N. Chaudhari, Sula Ndousse-Fetter, Alexander S. Banks, Jarrod A. Marto, Stephen C. Blacklow, A. Sloan Devlin
doi: https://doi.org/10.1101/640086
Arijit A. Adhikari
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Tom C. Seegar
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Scott B. Ficarro
2Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States
3Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States
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Megan D. McCurry
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Deepti Ramachandran
4Division of Endocrinology, Metabolism, and Diabetes, Beth Israel Deaconness Medical Center, Boston, Massachusetts 02115, United States
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Lina Yao
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Snehal N. Chaudhari
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Sula Ndousse-Fetter
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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Alexander S. Banks
4Division of Endocrinology, Metabolism, and Diabetes, Beth Israel Deaconness Medical Center, Boston, Massachusetts 02115, United States
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Jarrod A. Marto
2Department of Cancer Biology, Department of Oncologic Pathology, Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, United States
3Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, United States
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Stephen C. Blacklow
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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A. Sloan Devlin
1Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, United States
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  • For correspondence: sloan_devlin@hms.harvard.edu
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Abstract

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 in order to study the effects of bile acids on host physiology. Here, we report the development of a covalent pan-inhibitor of gut bacterial BSH. 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. Strikingly, 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.

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Posted May 17, 2019.
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Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases
Arijit A. Adhikari, Tom C. Seegar, Scott B. Ficarro, Megan D. McCurry, Deepti Ramachandran, Lina Yao, Snehal N. Chaudhari, Sula Ndousse-Fetter, Alexander S. Banks, Jarrod A. Marto, Stephen C. Blacklow, A. Sloan Devlin
bioRxiv 640086; doi: https://doi.org/10.1101/640086
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Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases
Arijit A. Adhikari, Tom C. Seegar, Scott B. Ficarro, Megan D. McCurry, Deepti Ramachandran, Lina Yao, Snehal N. Chaudhari, Sula Ndousse-Fetter, Alexander S. Banks, Jarrod A. Marto, Stephen C. Blacklow, A. Sloan Devlin
bioRxiv 640086; doi: https://doi.org/10.1101/640086

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