Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents.

Abstract

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.

• Authors: Yervand Eduard Karapetyan, Gian Franco Sferrazza, Minghai Zhou, Gregory Ottenberg, Timothy Spicer, Peter Chase, Mohammad Fallahi, Peter Hodder, Charles Weissmann, Corinne Ida Lasmézas
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 17 Pg. 7044-9 (Apr 23 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 23576755 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)

Chemical References

• Prions
• Astemizole
• Tacrolimus

Topics

• Animals
• Astemizole (pharmacology, therapeutic use)
• Autophagy (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Drug Discovery (methods)
• Drug Evaluation, Preclinical (methods)
• Fluorescence Resonance Energy Transfer (methods)
• High-Throughput Screening Assays (methods)
• Humans
• Kaplan-Meier Estimate
• Mice
• Mice, Inbred C57BL
• Prion Diseases (drug therapy)
• Prions (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Tacrolimus (pharmacology)