| Autor: |
Karapetyan YE; Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA., Sferrazza GF, Zhou M, Ottenberg G, Spicer T, Chase P, Fallahi M, Hodder P, Weissmann C, Lasmézas CI |
| Jazyk: |
angličtina |
| Zdroj: |
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Apr 23; Vol. 110 (17), pp. 7044-9. Date of Electronic Publication: 2013 Apr 01. |
| DOI: |
10.1073/pnas.1303510110 |
| Abstrakt: |
Prion diseases such as Creutzfeldt-Jakob disease (CJD) are incurable and rapidly fatal neurodegenerative diseases. Because prion protein (PrP) is necessary for prion replication but dispensable for the host, we developed the PrP-FRET-enabled high throughput assay (PrP-FEHTA) to screen for compounds that decrease PrP expression. We screened a collection of drugs approved for human use and identified astemizole and tacrolimus, which reduced cell-surface PrP and inhibited prion replication in neuroblastoma cells. Tacrolimus reduced total cellular PrP levels by a nontranscriptional mechanism. Astemizole stimulated autophagy, a hitherto unreported mode of action for this pharmacophore. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice. Astemizole is used in humans to treat seasonal allergic rhinitis in a chronic setting. Given the absence of any treatment option for CJD patients and the favorable drug characteristics of astemizole, including its ability to cross the blood-brain barrier, it may be considered as therapy for CJD patients and for prophylactic use in familial prion diseases. Importantly, our results validate PrP-FEHTA as a method to identify antiprion compounds and, more generally, FEHTA as a unique drug discovery platform. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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