A Gut-Restricted Lithocholic Acid Analog as an Inhibitor of Gut Bacterial Bile Salt Hydrolases

• DOI: 10.1021/acschembio.1c00192
• Publication Date: 2021-07-19T19:12:57Z
• Authors: Arijit A. Adhikari; Deepti Ramachandran; Snehal N. Chaudhari; Chelsea E. Powell; Wei Li; Megan D. McCurry; Alexander S. Banks; A. Sloan Devlin
• Keywords: Lithocholic acid; Deoxycholic acid

Bile acids play crucial roles in host physiology by acting both as detergents that aid digestion and signaling molecules bind to receptors. Gut bacterial bile salt hydrolase (BSH) enzymes perform the gateway reaction leading conversion of host-produced primary into bacterially modified secondary acids. Small molecule probes target BSHs will help elucidate causal these metabolites physiology. We previously reported development a covalent BSH inhibitor with low gut permeability. Here, we build on our previous findings describe second-generation gut-restricted enhanced potency, reduced off-target effects, durable vivo efficacy. Structure–activity relationship (SAR) studies focused acid core identified compound, AAA-10, containing C3-sulfonated lithocholic scaffold an alpha-fluoromethyl ketone warhead potent pan-BSH inhibitor. This compound inhibits activity mouse human fecal slurry, cultures, purified proteins displays toxicity against mammalian cells compared first generation compounds. Oral administration AAA-10 wild-type mice for 5 days resulted decrease abundance deoxycholic (DCA) (LCA) GI tract systemic exposure demonstrating is effective tool inhibiting modulating pool composition vivo.