Paper

Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry

Felix Felix Kopp, Ranhotra, Harmit, Costello, Cait M, Sun, Katherine, Nordstroem, Lars U, Li, Hao, Flannigan, Kyle L, Neary, Michelle C, Kemp, Jazmin S, Murray, Iain, Kortagere, Sandhya, Walton, William G, Mani, Sridhar, Dvorak, Zdenek, Matson, Adam, Karunaratne, Chamini, Stepankova, Martina, Chaterjee, Shirshendu, Wright, Dennis, Toporova, Lucia, Chandran, Aneesh, Brtko, Julius, Redinbo, Matthew R, Iveta Iveta Bartonkov, Gu, Haiwei, Hirota, Simon A, Poulikova, Karolina, Beck, Amanda, Vishveshwara, Saraswathi, Mun, Kyu Shik, Naren, Anjaparavanda P, Cavalluzzi, Maria M, Lentini, Giovanni, Wallace, Bret, Schon, Arne, Ryan Balfour Sartor, Julia Yue Cui, March, John C, Perdew, Gary H, Vrzalova, Aneta, Vyhlidalova, Barbora

2020

Overview

The human pregnane X receptor (PXR), a master regulator of drug metabolism, has important roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial off-target toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows to exploit previously unexplored parts of chemical space. Here we report functionalized indole-derivatives as first-in-class non-cytotoxic PXR agonists, as a proof-of-concept for microbial metabolite mimicry. The lead compound, FKK6, binds directly to PXR protein in solution, induces PXR specific target gene expression in, cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to mine underexploited regions of chemical space. Footnotes * Data included at the request of reviewers

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Biochemistry / Cytotoxicity / Drug discovery / Drug metabolism / Gene expression / Homeostasis / Indoles / Inflammation / Intestine / Ligands / Metabolites / Mimicry / Organoids