https://scholars.lib.ntu.edu.tw/handle/123456789/470056
標題: | Unnatural amino acid-substituted (hydroxyethyl)urea peptidomimetics inhibit γ-secretase and promote the neuronal differentiation of neuroblastoma cells | 作者: | Liao Y.-F. Wang B.-J. WEN-MING HSU Lee H. Liao C.-Y. Wu S.-Y. Cheng H.-T. Hu M.-K. |
公開日期: | 2007 | 卷: | 71 | 期: | 2 | 起(迄)頁: | 588-601 | 來源出版物: | Molecular Pharmacology | 摘要: | γ-Secretase, exhibiting characteristics of aspartyl protease, mediates the intramembranous proteolysis of β-amyloid precursor protein (APP) and Notch, and it is considered to be a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD). To identify compounds that block γ-secretase-mediated proteolysis, we used a highly sensitive cell-based reporter gene assay for γ-secretase in which Gal4/VP16-tagged C99-APP was expressed as the immediate substrate of γ-secretase, and Gal4/VP16-tagged APP intracellular domain released by the γ-secretase cleavage then activated the expression of the Gal4-driven luciferase reporter gene. Using this reporter assay, we demonstrated that the newly synthesized (hydroxyethyl)urea peptidomimetics, which contain unnatural amino acid moieties at positions P1′ and/or P3′, can effectively inhibit γ-secretase activity and significantly reduce Aβ production. The γ-secretase-dependent S3 cleavage of Notch was also consistently blocked by these (hydroxyethyl) ureas as evidenced by the decreased generation of the Notch intracellular domain, a prerequisite for the activation of Notch signaling. The inhibition of Notch signaling by active Jia compounds efficiently promotes the neuronal differentiation of neuroblastoma cells, intervening in tumorigenesis and the malignancy of neuroblastomas. Our results suggest that (hydroxyethyl) urea peptidomimetics containing unnatural amino acid substitutions could represent a novel class of γ-secretase inhibitors with enhanced stability, providing the basis for the further development of effective therapeutics for AD and neuroblastomas. Copyright ? 2007 The American Society for Pharmacology and Experimental Therapeutics. |
URI: | https://www.scopus.com/inward/record.uri?eid=2-s2.0-33846449879&doi=10.1124%2fmol.106.024299&partnerID=40&md5=eaa6a2b3215544e4ef02ffe9a1dbf9de https://scholars.lib.ntu.edu.tw/handle/123456789/470056 |
ISSN: | 0026-895X | DOI: | 10.1124/mol.106.024299 | SDG/關鍵字: | amino acid; amyloid beta protein; calreticulin; gamma secretase; gamma secretase inhibitor; hydroxyethylurea derivative; luciferase; Notch3 receptor; unclassified drug; Alzheimer disease; amino acid substitution; article; carcinogenesis; concentration response; controlled study; drug mechanism; drug synthesis; enzyme activity; human; human cell; nerve cell differentiation; neuroblastoma cell; nucleotide sequence; priority journal; protein degradation; protein expression; reporter gene; Amino Acids; Amyloid beta-Protein; Amyloid Precursor Protein Secretases; Antineoplastic Agents; Cell Differentiation; Cell Line; Cell Line, Tumor; Humans; Hydroxyurea; Inhibitory Concentration 50; Molecular Mimicry; Neuroblastoma; Neurons; Peptides; Receptors, Notch |
顯示於: | 醫學系 |
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