Tailoring obeticholic acid activity by iridium(III) complex conjugation to develop a farnesoid X receptor probe.

INTRODUCTION: The farnesoid X receptor (FXR) is a crucial regulator in the intestine, maintaining bile acid homeostasis. Inhibiting intestinal FXR shows promise in managing inflammatory bowel and liver diseases by reducing bile acid accumulation. Additionally, changes in FXR expression could serve as a potential biomarker for intestinal diseases. Therefore, developing an imaging probe for FXR holds significant potential for the early detection, simultaneous treatment, and monitoring of FXR-related diseases. OBJECTIVES: The study aimed to develop a bioimaging probe for FXR by conjugating obeticholic acid (OCA), an FXR agonist, to an iridium(III) complex, and to investigate its application for targeting FXR in intestinal cells. METHODS: OCA was conjugated to an iridium(III) complex to generate the novel complex 1. The effect of complex 1 on FXR activity, nuclear translocation, and downstream targets was investigated in intestinal epithelial cells using various biochemical and cellular assays. Additionally, the photophysical properties of complex 1 were assessed for FXR imaging. RESULTS: Complex 1 retained the desirable photophysical properties for monitoring FXR in intestinal cells while reversing OCA's activity from agonistic to antagonistic. It disrupted FXR-RXR heterodimerization, inhibited FXR nuclear translocation, and downregulated downstream targets responsible for bile acid absorption, transport, and metabolism in intestinal epithelial cells. CONCLUSION: The study successfully developed an imaging probe and modulator of FXR by conjugating OCA to an iridium(III) complex. Complex 1 retained the favorable photophysical properties of the iridium(III) complex, while reversing OCA's activity from agonistic to antagonistic. The findings highlight the exciting application of using metals to tailor the activity of nuclear receptor modulators in living systems.