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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: Targeting the pregnane X receptor using microbial metabolite mimicry.

Authors: Dvořák, Zdeněk; Kopp, Felix; Costello, Cait M; Kemp, Jazmin S; Li, Hao; Vrzalová, Aneta; Štěpánková, Martina; Bartoňková, Iveta; Jiskrová, Eva; Poulíková, Karolína; Vyhlídalová, Barbora; Nordstroem, Lars U; Karunaratne, Chamini V; Ranhotra, Harmit S; Mun, Kyu Shik; Naren, Anjaparavanda P; Murray, Iain A; Perdew, Gary H; Brtko, Julius; Toporova, Lucia; Schön, Arne; Wallace, Bret D; Walton, William G; Redinbo, Matthew R; Sun, Katherine; Beck, Amanda; Kortagere, Sandhya; Neary, Michelle C; Chandran, Aneesh; Vishveshwara, Saraswathi; Cavalluzzi, Maria M; Lentini, Giovanni; Cui, Julia Yue; Gu, Haiwei; March, John C; Chatterjee, Shirshendu; Matson, Adam; Wright, Dennis; Flannigan, Kyle L; Hirota, Simon A; Sartor, Ryan Balfour; Mani, Sridhar

Published In EMBO Mol Med, (2020 Apr 07)

Abstract: The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential 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 exploiting 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 (Felix Kopp Kortagere 6), 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 underexploited regions of chemical space.

PubMed ID: 32153125 Exiting the NIEHS site

MeSH Terms: Animals; Cells, Cultured; Cytokines; Humans; Inflammation; Intestines; Ligands; Mice; Molecular Mimicry*; Organoids; Pregnane X Receptor/chemistry*

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