Sunday, May 19, 2019

Development of a Covalent Inhibitor of Gut Bacterial Bile Salt Hydrolases [@DevlinLab]

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, 2019
doi: 10.1101/640086

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.

Thiol Reactivity of N-Aryl α-Methylene-γ-lactams: Influence of the Guaianolide Structure [@KayBrummond]

 Daniel P. Dempe, Chong-Lei Ji, Peng Liu, and Kay M. Brummond The Journal of Organic Chemistry, 2020 DOI: 10.1021/acs.joc.2c01530 The α-meth...