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J. Biol. Chem., Vol. 276, Issue 36, 33309-33312, September 7, 2001

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ACCELERATED PUBLICATION
Peptide Mimetic HIV Protease Inhibitors Are Ligands for the Orphan Receptor SXR^*

Isabelle Dussault, Min Lin, Kevin Hollister, Eric H. Wang, Timothy W. Synold^§, and Barry Marc Forman^¶

From the  Division of Molecular Medicine, The Gonda Diabetes and Genetic Research Center and the ^§ Department of Medical Oncology and Therapeutics Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010

The orphan nuclear receptor SXR coordinately regulates drug clearance in response to a wide variety of xenobiotic compounds. This signaling system protects the body from exposure to toxic compounds; however, it can also pose a severe barrier to drug therapy. We now demonstrate that the human immunodeficiency virus (HIV) protease inhibitor ritonavir binds SXR and activates its target genes. This represents an example of a commonly used therapeutic agent that effectively activates SXR. We also show that other protease inhibitors are weaker (saquinavir) or unable to activate SXR (nelfinavir, indinavir) thus defining analogs that fail to induce SXR-regulated clearance pathways. Interestingly, HIV protease inhibitors are distinct from previously known SXR ligands in that they are peptide mimetic compounds. This expands the ligand specificity of SXR to include this unique chemical class whose pharmaceutical significance is expanding. Finally, we show that SXR ligands activate expression of multiple resistance protein 2, a critical regulator of bile flow and biliary drug excretion. These findings have important implications for the role of SXR in regulating drug clearance and hepatic disorders associated with impaired bile flow.

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