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The Nuclear Receptor-Coactivator Interaction Surface as a Target for Peptide Antagonists of the Peroxisome Proliferator-Activated Receptors

Department of Pharmacology and Cancer Biology (N.B.M., M.A.D., M.S.J., J.M.H., D.P.M.), Duke University Medical Center, Durham, North Carolina 27710; Department of Biochemical and Cellular Targets (T.B.S.), Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, North Carolina 27709; and Department of Chemistry (J.E.A.), Duke University, Durham, North Carolina 27708

Address all correspondence and requests for reprints to: Donald P. McDonnell, Duke University Medical Center, Pharmacology and Cancer Biology, Box 3813, Durham, North Carolina 27710. E-mail: donald.mcdonnell{at}duke.edu.

The peroxisome proliferator-activated receptors (PPAR, PPAR, and PPAR) constitute a family of nuclear receptors that regulates metabolic processes involved in lipid and glucose homeostasis. Although generally considered to function as ligand-regulated receptors, all three PPARs exhibit a high level of constitutive activity that may result from their stimulation by intracellularly produced endogenous ligands. Consequently, complete inhibition of PPAR signaling requires the development of inverse agonists. However, the currently available small molecule antagonists for the PPARs function only as partial agonists, or their efficacy is not sufficient to inhibit the constitutive activity of these receptors. Due to the lack of efficacious antagonists that interact with the ligand-binding domain of the PPARs, we decided to target an interaction that is central to nuclear receptor-mediated gene transcription: the nuclear receptor-coactivator interaction. We utilized phage display technology to identify short LXXLL-containing peptides that bind to the PPARs. Analysis of these peptides revealed a consensus binding motif consisting of HPLLXXLL. Cross-screening of these peptides for binding to other nuclear receptors enabled the identification of a high-affinity PPAR-selective peptide that has the ability to repress PPAR1-dependent transcription of transfected reporter genes. Most importantly, when introduced into HepG2 cells, the peptide inhibited the expression of endogenous PPAR1 target genes, adipose differentiation-related protein and mitochondrial 3-hydroxy-3-methylglutaryl coenzyme A synthase 2. This work lends support for the rational development of peptidomimetics that block receptor-mediated transcription by targeting the nuclear receptor-coactivator interaction surface.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  PPARδ  |  PPARγ  |  LXRα  |  HNF4α  |  RXRα  |  ERα  |  ERβ  |  ERRα  |  ERRβ  |  ERRγ  |  PR  |  AR  |  LRH-1

Ligands:   Rifampicin  |  22α-Hydroxycholesterol  |  GW 7647  |  all-trans-Retinoic acid  |  Calcitriol  |  Dexamethasone  |  17β-Estradiol  |  9-cis-Retinoic acid  |  Thyroid hormone  |  Rosiglitazone  |  R1881  |  R5020

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