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

作者：Karapetyan Yervand Eduard; Sferrazza Gian Franco; Zhou Minghai; Ottenberg Gregory; Spicer Timothy; Chase Peter; Fallahi Mohammad; Hodder Peter; Weissmann Charles^*; Lasmezas Corinne Ida

来源：Proceedings of the National Academy of Sciences, 2013, 110(17): 7044-7049.

DOI：10.1073/pnas.1303510110

• protein misfolding
• high-throughput screening
• prion therapeutics

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.

• 出版日期2013-4-23