Scientists have identified a pair of drugs already approved for human use that show antiprion activity, and one of them may hold promise in treating fatal disorders, such as Creutzfeldt-Jakob disease (the human equivalent of mad cow disease), says the team at the Florida campus of The Scripps Research Institute. The two compounds are already marketed as the drugs tacrolimus and astemizole.
The team developed a screening technique, the PrP–FRET-enabled high-throughput assay (PrP–FEHTA), to uncover compounds that decrease the amount of the normal form of the prion protein (PrP, which becomes distorted by the disease) at the cell surface. The scientists found that tacrolimus and astemizole reduced PrP on cell surfaces by approximately 70% in the screening and follow-up tests.
Tacrolimus is an immune suppressant widely used in organ transplantation. Tacrolimus could prove problematic as an antiprion drug, however, because of issues including possible neurotoxicity, the reseachers report. However, astemizole is an antihistamine that has potential for use as an antiprion drug. While withdrawn voluntarily from the U.S. over-the-counter market in 1999 because of rare cardiac arrhythmias when used in high doses, it has been available in generic form in more than 30 countries and has a well-established safety profile. Astemizole not only crosses the blood-brain barrier, but works effectively at a relatively low concentration, the team says. Astemizole, but not tacrolimus, prolonged the survival time of prion-infected mice.
Scripps professor Corinne Lasmézas, Ph.D., noted that astemizole appears to stimulate autophagy, the process by which cells eliminate unwanted components. “Autophagy is involved in several protein misfolding neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s diseases,” she says. “So future studies on the mode of action of astemizole may uncover potentially new therapeutic targets for prion diseases and similar disorders.”
The study noted that eliminating cell surface PrP expression could also be a potentially new approach to treat Alzheimer’s disease, which is characterized by the build-up of amyloid β plaque in the brain. PrP is a cell surface receptor for Aβ peptides and helps mediate a number of critical deleterious processes in animal models of the disease.
The scientists also note that their results validate PrP-FEHTA as a method to identify antiprion compounds and FEHTA as a drug discovery platform.
The study was published this week online ahead of print by the journal Proceedings of the National Academy of Sciences. The article is called “Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents”.