2013/04/01 by Yervand E Karapetyan, Gian Franco Sferrazza, Minghai Zhou +7 · 3 citations
Biochemistry, Genetics and Molecular Biology · Immunology and Microbiology · Medicine · Neuroscience · #Astemizole #Autophagy #Bioinformatics #Biology #Disease #Drug #Drug discovery #Genetics #HIV Research and Treatment #Immunology #Internal medicine #Medicine #Neurological diseases and metabolism #Pathology #Pharmacology #Pharmacophore #Prion Diseases and Protein Misfolding #Tacrolimus #Transplantation #Virology
paper · pdf · doi:10.1073/pnas.1303510110
openalex publication_date 2013/04/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
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.