title: 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.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA.
authors.forename: Yervand Eduard
authors.initials: YE
authors.lastname: Karapetyan
authors.forename: Gian Franco
authors.initials: GF
authors.lastname: Sferrazza
authors.forename: Minghai
authors.initials: M
authors.lastname: Zhou
authors.forename: Gregory
authors.initials: G
authors.lastname: Ottenberg
authors.forename: Timothy
authors.initials: T
authors.lastname: Spicer
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.forename: Charles
authors.initials: C
authors.lastname: Weissmann
authors.forename: Corinne Ida
authors.initials: CI
authors.lastname: Lasmézas
mesh_terms: D000818:Animals; D016589:Astemizole / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D057166:High-Throughput Screening Assays / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D017096:Prion Diseases / Q000188:drug therapy*; D011328:Prions / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D011328:Prions; D016589:Astemizole; D016559:Tacrolimus