Alzheimer's disease drug discovery targeted to the APP mRNA 5'untranslated region.
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.
Rogers
Jack T
JT
Genetics and Aging Unit, Massachusetts General Hospital Harvard Medical School, Charlestown 02129-4404, USA. Rogersj@helix.mgh.harvard.edu
Randall
Jeffrey D
JD
Eder
Paul S
PS
Huang
Xudong
X
Bush
Ashley I
AI
Tanzi
Rudolph E
RE
Venti
Amanda
A
Payton
Sandra M
SM
Giordano
Tony
T
Nagano
Seiichi
S
Cahill
Catherine M
CM
Moir
Robert
R
Lahiri
Debomoy K
DK
Greig
Nigel
N
Sarang
Satinder Singh
SS
Gullans
Steven R
SR
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
D020121:5' Untranslated Regions; D016564:Amyloid beta-Protein Precursor; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D008156:Luciferases