PT  - JOURNAL ARTICLE
AU  - Zdeněk Dvořák
AU  - Felix Kopp
AU  - Cait M. Costello
AU  - Jazmin S. Kemp
AU  - Hao Li
AU  - Aneta Vrzalová
AU  - Martina Štěpánková
AU  - Iveta Bartoňková
AU  - Eva Jiskrová
AU  - Karolína Poulíková
AU  - Barbora Vyhlídalová
AU  - Lars U. Nordstroem
AU  - Chamini Karunaratne
AU  - Harmit Ranhotra
AU  - Kyu Shik Mun
AU  - Anjaparavanda P. Naren
AU  - Iain Murray
AU  - Gary H. Perdew
AU  - Julius Brtko
AU  - Lucia Toporova
AU  - Arne Schon
AU  - William G. Wallace
AU  - William G. Walton
AU  - Matthew R. Redinbo
AU  - Katherine Sun
AU  - Amanda Beck
AU  - Sandhya Kortagere
AU  - Michelle C. Neary
AU  - Aneesh Chandran
AU  - Saraswathi Vishveshwara
AU  - Maria M. Cavalluzzi
AU  - Giovanni Lentini
AU  - Julia Yue Cui
AU  - Haiwei Gu
AU  - John C. March
AU  - Shirshendu Chaterjee
AU  - Adam Matson
AU  - Dennis Wright
AU  - Kyle L. Flannigan
AU  - Simon A. Hirota
AU  - R. Balfour Sartor
AU  - Sridhar Mani
TI  - Targeting the Pregnane X Receptor Using Microbial Metabolite Mimicry
AID  - 10.1101/792671
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 792671
4099  - http://biorxiv.org/content/early/2020/01/03/792671.short
4100  - http://biorxiv.org/content/early/2020/01/03/792671.full
AB  - 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.