Antagonizing the Bile-Acid Receptor

HIGHLIGHTS

IN BRIEF

CARDIOVASCULAR DISEASES

First experience with direct factor Xa inhibition HYPOLIPIDAEMIC DRUGS in patients with stable coronary disease. A pharmacokinetic and pharmacodynamic evaluation Dyke, C. K. et al. Circulation 2002 Apr 29 Antagonizing the bile-acid receptor (doi: 10.1161/01.CIR.0000016351.12759.52) Inhibition of factor Xa — which has a key role in the formation For centuries, the gum resin of the domain of the steroid-receptor coacti- of blood clots — might be more effective and safer than current tree Commiphora mukul (guggulu in vator-1 is specifically recruited to the treatments, such as heparin and warfarin, for preventing the sanskrit) has been used in Ayurvedic FXR ligand-binding domain. In an formation of potentially life-threatening blood clots in patients medicine to treat obesity and lipid elegant demonstration, FRET analysis with coronary artery disease. In this Phase Ib trial involving disorders, and since 1997, the resin revealed that CDCA and guggul- 73 patients, the small-molecule factor Xa inhibitor DX-9065a extract — gugulipid — has been sterone directly compete for the lig- (Daiichi Pharmaceutical Company) was shown to be safe in approved to treat hyperlipidaemia in and-binding domain. Guggulsterone patients with stable coronary disease who were receiving standard India. Guggulsterone, one of the did not activate or inhibit transactiva- therapy (for example, aspirin, beta-blockers and statins), paving compounds that is present in tion by several other receptors that are the way for larger clinical studies with this new drug class. gugulipid, reduces cholesterol levels. associated with lipid metabolism. In Science, Moore and colleagues Finally, the authors showed that it is COMPUTATIONAL CHEMISTRY show that the molecular mechanism the FXR antagonistic activity of gug- by which cholesterol is lowered is gulsterone that is required for its A virtual screening method for prediction of the hERG through antagonism of the farnesoid hypolipidaemic effects. The choles- potassium channel liability of compound libraries X receptor (FXR). terol-lowering effect of the drug was Roche, O. et al. ChemBioChem 3, 455–459 (2002) Cholesterol is tightly regulated at absent in Fxr-deficient mice. Inter- Compounds that block the hERG potassium channel cause QT many levels. One way that cholesterol estingly, Fxr-deficient mice do not prolongation, a disorder of cardiac-action-potential repolarization is released is in the form of bile acids. have decreased cholesterol levels, that can lead to potentially lethal cardiac arrhythmias. More than When these acids are high, a negative- which could possibly be due to 70 common drugs have been shown to have this serious side effect. feedback loop is activated to reduce chronic compensatory pathways. Using various techniques to find appropriate molecular cholesterol production by the liver. Although a standardized prepara- descriptors, Roche et al. developed a virtual-screening method for This negative regulation is mediated tion of gugulipid has never been predicting hERG affinity, which could classify known blockers and by the bile-acid nuclear-hormone compared directly with other non-blockers with 71% and 93% accuracy, respectively. receptor FXR. As FXR can be activated hypolipidaemic drugs, such as statins, by compounds that are structurally gugulipid seems to have comparable BLOOD DISEASES unrelated to bile acids, and guggul- efficacy and fewer side effects. Its sterone decreases hepatic cholesterol mechanism of action is different from Treatment of hypereosinophilic syndrome with imatinib levels in rodent models, the authors that of the statins, so it is likely that mesilate proposed that this plant product could gugulipid would be useful in combi- Gleich, G. J. et al. Lancet 359, 1577–1578 (2002) act by modulating FXR activity. nation with them, or in individuals Hypereosinophilic syndrome (HES) is a potentially fatal blood The effect of guggulsterone on who have problems tolerating statins. disease that is characterized by an increase in inflammatory white FXR activity was tested using transient However, the effect on FXR that was blood cells, which results in organ damage. Drugs used in patients transfections with a synthetic FXR- described in the paper suggests that with chronic myelogenous leukemia (CML) have been used in responsive reporter plasmid. The guggulsterone might induce drug HES, but with limited effect. Gleich et al. tested Gleevec (imatinib compound strongly inhibited FXR metabolism and thereby decrease the mesilate), the recently approved breakthrough treatment for CML, activation by the most potent of the effectiveness of other drugs. This in five patients with HES, and four showed marked improvements; bile-acid agonists — chenodeoxy- work has implications for other rela- however, the underlying mechanism remains to be elucidated. cholic acid (CDCA) — in a dose- tively promiscuous nuclear-hormone dependent manner. Similar results receptors that might mediate the bio- were seen with the promoter of the logical effects of different natural GENOMICS orphan receptor SHP (short het- products. Further characterization of Complete genome sequence of the model erodimer partner), which contains an these effects could identify agents actinomycete Streptomyces coelicolor A3(2) FXR/retinoid X receptor heterodimer- with desirable therapeutic activities. 417 binding site and is induced by bile Melanie Brazil Bentley, S. D. et al. Nature , 141–147 (2002) acids. To test whether guggulsterone References and links Actinomycetes, such as Streptomyces coelicolor, produce two-thirds directly antagonizes FXR, a fluores- ORIGINAL RESEARCH PAPER Urizar, N. L. et al. A natural product that lowers cholesterol as an of the natural antibiotics in use, and also many anticancer agents. cence resonance energy transfer antagonist ligand for the FXR. Science 2002 May 2 The genome sequence of S. coelicolor, the model actinomycete, (FRET) assay was used. In the pres- (doi: 10.1126/science.1072891) should facilitate experiments aimed at manipulating the WEB SITES Moore’s laboratory: ence of the agonist CDCA, a peptide http://public.bcm.tmc.edu/mcb/faculty/moore_ biosynthetic gene clusters of therapeutic natural products to that contained the receptor-binding d.html produce novel agents with potentially improved activities.