LXXLL peptide mimetics as inhibitors of the interaction of vitamin D receptor with coactivators
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- 作者：Yusuke Mita ; Kosuke Dodo ; Tomomi Noguchi-Yachide ; Hiroyuki Miyachi ; Makoto Makishima ; Yuichi Hashimoto ; Minoru Ishikawa
- 关键词：Vitamin D ; Antagonist ; Co-factor ; Nuclear receptor ; Non-peptide ; Molecular design ; Protein interaction inhibitor
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2010
- 出版时间：1 March 2010
- 年：2010
- 卷：20
- 期：5
- 页码：1712-1717
- 全文大小：595 K
文摘
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 α-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 IC50 of 20 μM. 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 α-mediated transcription, indicating that it is not a non-selective inhibitor of other nuclear receptors.