1. Alzheimer's disease drug discovery targeted to the APP mRNA 5'untranslated region.
- Author
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Rogers JT, Randall JD, Eder PS, Huang X, Bush AI, Tanzi RE, Venti A, Payton SM, Giordano T, Nagano S, Cahill CM, Moir R, Lahiri DK, Greig N, Sarang SS, and Gullans SR
- Subjects
- Alzheimer Disease metabolism, Amyloid beta-Protein Precursor genetics, Drug Approval, Humans, Luciferases genetics, Protein Biosynthesis, Transfection, Tumor Cells, Cultured, United States, 5' Untranslated Regions drug effects, Alzheimer Disease drug therapy, Amyloid beta-Protein Precursor drug effects, Amyloid beta-Protein Precursor metabolism, Pharmaceutical Preparations, RNA, Messenger drug effects
- 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.
- Published
- 2002
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