Targeting the pregnane X receptor using microbial metabolite mimicry.

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.