title: Alzheimer's disease drug discovery targeted to the APP mRNA 5'untranslated region.
abstract: We performed a screen for drugs that specifically interact with the 5' untranslated region of the mRNA coding for the Alzheimer's Amyloid Precursor Protein (APP). Using a transfection based assay, in which APP 5'UTR sequences drive the translation of a downstream luciferase reporter gene, we have been screening for new therapeutic compounds that already have FDA approval and are pharmacologically and clinically well-characterized. Several classes of FDA-pre-approved drugs (16 hits) reduced APP 5'UTR-directed luciferase expression (> 95% inhibition of translation). The classes of drugs include known blockers of receptor ligand interactions, bacterial antibiotics, drugs involved in lipid metabolism, and metal chelators. These APP 5'UTR directed drugs exemplify a new strategy to identify RNA-directed agents to lower APP translation and A beta peptide output for Alzheimer's disease therapeutics.
authors.affiliation: Genetics and Aging Unit, Massachusetts General Hospital Harvard Medical School, Charlestown 02129-4404, USA. Rogersj@helix.mgh.harvard.edu
authors.forename: Jack T
authors.initials: JT
authors.lastname: Rogers
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Randall
authors.forename: Paul S
authors.initials: PS
authors.lastname: Eder
authors.forename: Xudong
authors.initials: X
authors.lastname: Huang
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.forename: Rudolph E
authors.initials: RE
authors.lastname: Tanzi
authors.forename: Amanda
authors.initials: A
authors.lastname: Venti
authors.forename: Sandra M
authors.initials: SM
authors.lastname: Payton
authors.forename: Tony
authors.initials: T
authors.lastname: Giordano
authors.forename: Seiichi
authors.initials: S
authors.lastname: Nagano
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Cahill
authors.forename: Robert
authors.initials: R
authors.lastname: Moir
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Nigel
authors.initials: N
authors.lastname: Greig
authors.forename: Satinder Singh
authors.initials: SS
authors.lastname: Sarang
authors.forename: Steven R
authors.initials: SR
authors.lastname: Gullans
mesh_terms: D020121:5' Untranslated Regions / Q000187:drug effects*; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism*; D017277:Drug Approval; D006801:Humans; D008156:Luciferases / Q000235:genetics; D004364:Pharmaceutical Preparations; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000187:drug effects*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014481:United States
chemical_list: D020121:5' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D008156:Luciferases