LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators.
Suppression of vitamin D receptor (VDR)-mediated transcription is expected be of therapeutic value in Paget's disease. Once an agonist activates VDR, recruitment of additional coactivator proteins is essential for transcription. Neither non-secosteroidal VDR antagonists nor non-peptide coactivator binding inhibitors for VDR have been reported so far. Based on the X-ray structure of VDR and an LXXLL-containing peptide fragment of the coactivator (where L is leucine and X is any amino acid), which adopts a partially alpha-helical conformation, benzodiazepine molecules were rationally designed as non-peptide coactivator mimetics. TR-FRET assay showed that the synthesized compounds inhibited the interaction between VDR and a coactivator peptide fragment. Compound 2 showed an IC(50) of 20microM. Compound 2 also inhibited VDR-mediated transcription, and this activity was independent of the concentration of co-existing agonist. Furthermore, compound 2 did not inhibit estrogen receptor alpha-mediated transcription, indicating that it is not a non-selective inhibitor of other nuclear receptors.
Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
Yusuke
Y
Mita
Kosuke
K
Dodo
Tomomi
T
Noguchi-Yachide
Hiroyuki
H
Miyachi
Makoto
M
Makishima
Yuichi
Y
Hashimoto
Minoru
M
Ishikawa
D000595:Amino Acid Sequence; D001569:Benzodiazepines / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D010001:Osteitis Deformans / Q000188:drug therapy; D010455:Peptides / Q000737:chemistry* / Q000627:therapeutic use; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015533:Transcriptional Activation
D010455:Peptides; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D001569:Benzodiazepines