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Related Experiment Video

Updated: Jun 24, 2026

Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Rifamycin Structural Modifications Attenuate PXR Binding and CYP3A4 Induction.

Amir George1, Tian Lan2, Andrew D Huber3

  • 1Department of Pharmacology, Physiology, and Neuroscience, Rutgers University─New Jersey Medical School, Newark, New Jersey 07103, United States.

Journal of Medicinal Chemistry
|June 23, 2026
PubMed
Summary
This summary is machine-generated.

Modifying rifamycins, like rifabutin, can reduce drug interactions. New analogs bind the pregnane X receptor (PXR) but decrease its activation, potentially leading to safer antimycobacterial therapies.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Drug Discovery

Background:

  • Rifamycins are crucial for antimycobacterial treatment.
  • Clinical use is limited by drug-drug interactions mediated by pregnane X receptor (PXR) activation.
  • PXR induces drug-metabolizing enzymes like CYP3A4, accelerating drug clearance.

Purpose of the Study:

  • To investigate structural modifications of rifamycins to reduce PXR-mediated drug interactions.
  • To understand the relationship between rifamycin binding to PXR and its transcriptional activation.
  • To develop rifamycin analogs with attenuated CYP3A4 induction.

Main Methods:

  • Design and synthesis of C25-modified rifabutin analogs.
  • Evaluation of PXR binding affinity and transcriptional activation.
  • Assessment of pharmacological profiles and CYP3A4 induction.
  • Molecular dynamics simulations to elucidate structural interactions.

Main Results:

  • Several rifabutin analogs maintained PXR binding affinity but exhibited reduced CYP3A4 induction.
  • These analogs acted as PXR antagonists or inverse agonists, decoupling binding from activation.
  • Molecular dynamics suggested C25 modifications disrupt PXR α12 helix positioning.

Conclusions:

  • Conservative rifamycin modifications can convert PXR agonists into antagonists or inverse agonists.
  • This offers a structure-guided approach to develop rifamycins with reduced CYP3A4 induction.
  • Potential for safer antimycobacterial therapies with fewer drug-drug interactions.