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Nuclear receptors, or NRs, are unique transcription factors that regulate gene transcription and affect the cellular pathways involved in reproduction, development, or metabolism. Their ability to be stimulated by small lipophilic ligands and control vital cellular processes makes them ideal drug targets. Nearly 10-15% of currently prescribed drugs target these receptors.
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Drugs target macromolecules to modify ongoing cellular processes. Primary drug targets include receptors, ion channels, transporters, and enzymes.
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Related Experiment Video

Updated: Dec 26, 2025

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Targeting the pregnane X receptor using microbial metabolite mimicry.

Zdeněk Dvořák1, Felix Kopp2, Cait M Costello3

  • 1Department of Cell Biology and Genetics, Palacký University, Olomouc, Czech Republic.

EMBO Molecular Medicine
|March 11, 2020
PubMed
Summary

Microbial metabolite mimicry offers a novel drug discovery strategy. Functionalized indoles, like FKK6, are non-cytotoxic PXR agonists that reduce inflammation, validating this approach.

Keywords:
drugsmicrobial metabolitemimicspregnane X receptortherapy

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Screening Peptides that Activate MRGPRX2 using Engineered HEK Cells
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Area of Science:

  • Pharmacology
  • Drug Metabolism
  • Microbiology

Background:

  • The human pregnane X receptor (PXR) regulates drug metabolism, intestinal homeostasis, and inflammation.
  • Current PXR ligands exhibit significant off-target toxicity.
  • Microbial indole metabolites are known PXR ligands.

Purpose of the Study:

  • To explore microbial metabolite mimicry as a novel drug discovery strategy.
  • To identify and characterize non-cytotoxic PXR agonists.
  • To validate this approach for therapeutic potential in inflammation.

Main Methods:

  • Design and synthesis of functionalized indole derivatives.
  • In vitro binding assays with PXR protein.
  • Gene expression analysis in cells and human organoids.
  • In vivo studies in mice expressing human PXR.

Main Results:

  • Identified functionalized indoles as first-in-class non-cytotoxic PXR agonists.
  • The lead compound FKK6 directly binds PXR and induces target gene expression.
  • FKK6 repressed pro-inflammatory cytokine production and abrogated inflammation in vivo.

Conclusions:

  • Microbial metabolite mimicry is a viable drug discovery strategy.
  • Functionalized indoles represent a promising new class of PXR agonists.
  • FKK6 demonstrates therapeutic potential for PXR-mediated inflammatory conditions.