Drug discovery targeted to the Alzheimer's APP mRNA 5'-untranslated region: the action of paroxetine and dimercaptopropanol.
We screened for drugs that specifically interact with the 5'-untranslated region of the mRNA encoding the Alzheimer's amyloid precursor protein (APP). Our goal was to use newly discovered APP 5' UTR directed compounds to limit amyloid-beta (Abeta)-peptide output in cell culture systems. The APP 5' UTR folds into a stable RNA secondary structure (Gibbs free energy: DeltaG = -54.9 kcal/mol) and is an important regulator of the amount of APP translated in response to IL-1 (Nilsson et al., 1998; Rogers et al., 1999) and iron (Rogers et al., 2002). Seventeen drug "hits" were identified from a library of 1,200 FDA preapproved drugs (Rogers et al., 2002). Six of the original 17 compounds were validated for their capacity to suppress reporter gene expression in stable neuroblastoma transfectants expressing the dicistronic reporter construct shown in Fig. 2. These six leads suppressed APP 5' UTR driven luciferase translation while causing no effect on the translation of dicistronic GFP gene translated from a viral IRES (negative control to ensure specificity during drug screens). In this report, we show that paroxetine (serotonin reuptake blocker) and dimercaptopropanol (Hg chelator) exerted significant effects on APP expression (steady-state levels of APP), whereas Azithromycin altered APP processing. None of these three compounds altered APLP-1 expression. In the future, we will identify further novel compounds that influence Abeta levels, either via translation inhibition or by changing the activity of proteins coupled between APP translation and APP processing.
D020121:5' Untranslated Regions / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000235:genetics*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017963:Azithromycin / Q000494:pharmacology; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D004112:Dimercaprol / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D017930:Genes, Reporter / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008156:Luciferases / Q000235:genetics; D017374:Paroxetine / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D020121:5' Untranslated Regions; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000900:Anti-Bacterial Agents; D017963:Azithromycin; D002614:Chelating Agents; D004112:Dimercaprol; D008156:Luciferases; D017374:Paroxetine; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors