Antihypertensive drug guanabenz is active in vivo against both yeast and mammalian prions

Abstract

Background: Prion-based diseases are incurable transmissible neurodegenerative disorders affecting animals and humans. Methodology/Principal Finding: Here we report the discovery if the in vivo antiprion activity of Guanabenz (GA), an agonist of α2-adrenergic receptors routinely used in human medicine as an antihypertensive drug. We isolated GA in a screen for drugs active in vivo against two different yeast proins using a previously described yeast-based two steps assay. GA was then shown to promote ovine PrpSc clearance in a cell-based assay. These effects are very specificas evidenced by the lack of activity of some GA analogues that we generated. GA antiprion activity does not involve its agonist activity on α2-adrenergic receptors as other chemically close anti-hypertensive agents possessing related mechanism of action were found inactive against prions. Finally, GA showed activity in a transgenic mouse-based in vivo assay for ovine prion propagation, prologing slightly but significantly the survival of treated animals. Conclusion/Significance: GA thus adds to the short list of compounds active in vivo in animal models for the treatment of prion-based disease. Because it has been administrated for many years to treat hypertension on a daily basis, without major side-effects, our results suggest that it could be evaluated in human as a potential treatment for prion-based diseases. © 2008 Tribouillard-Tanvier et al.