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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.

SUBMITTER: Karapetyan YE

PROVIDER: S-EPMC3637718 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

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

Karapetyan Yervand Eduard YE Sferrazza Gian Franco GF Zhou Minghai M Ottenberg Gregory G Spicer Timothy T Chase Peter P Fallahi Mohammad M Hodder Peter P Weissmann Charles C Lasmézas Corinne Ida CI

Proceedings of the National Academy of Sciences of the United States of America 20130401 17

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 neuro ...[more]

PMID: 23576755

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

Publications

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

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