Peptide mimetic HIV protease inhibitors are ligands for the orphan receptor SXR

The orphan nuclear receptor SXR coordinately regulates drug clearance in re sponse to a wide variety of xenobiotic compounds. This signaling system pro tects the body from exposure to toxic compounds; however, it can also pose a severe barrier to drug therapy. We now demonstrate that the human immunod eficiency 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 inh ibitors are weaker (saquinavir) or unable to activate SXR (nelfinavir, indi navir) thus defining analogs that fail to induce SXR-regulated clearance pa thways. 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 imp lications for the role of SXR in regulating drug clearance and hepatic diso rders associated with impaired bile flow.