Targeting the pregnane X receptor using microbial metabolite mimicry.

EMBO Molecular Medicine
Zdenek DvorakSridhar Mani

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.

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Citations

Apr 15, 2020·International Journal of Molecular Sciences·Barbora VyhlídalováZdeněk Dvořák
Jul 28, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Serge MignaniGiovanni Lentini
Aug 19, 2020·International Journal of Molecular Sciences·Tania RossiFrancesca Pirini
Feb 15, 2021·European Journal of Medicinal Chemistry·Zdeněk DvořákSridhar Mani
Jan 18, 2021·Current Opinion in Immunology·Teresa ZelanteLuigina Romani
Oct 25, 2020·Trends in Pharmacological Sciences·Zdeněk DvořákSridhar Mani
Sep 25, 2020·European Journal of Medicinal Chemistry·Elizabeth Goya-JorgeRosa M Giner
Apr 16, 2021·Medicinal Research Reviews·Yusha Luo, Tingting Zhou
Apr 19, 2021·Trends in Molecular Medicine·Xiao-Jing GuanHai-Ping Hao
Jun 18, 2021·Biological Reviews of the Cambridge Philosophical Society·Prasun KumarJintae Lee
Jun 30, 2021·Biochimie·Kristyna Krasulova, Peter Illes

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Methods Mentioned

BETA
nuclear translocation
immunoprecipitation
PCR
transfection
ChIP
isothermal titration calorimetry
biopsies
Assay
gel filtration

Software Mentioned

DiscoverX
TREE
ligX
GraphPad Prism
SDS
GraphPad
Volocity
Synthego Inference of CRISPR Edits
ProteinSimple
MOE

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