Infectious Disorders - Drug Targets

(Formerly Current Drug Targets - Infectious Disorders)

Jean-Marc Sabatier  
Laboratoire ERT 62 'Ingénierie des peptides à visée thérapeutique' 
Université de la Méditerranée
Faculté de Médecine Nord
Boulevard Pierre Dramard
13916 - MARSEILLE, Cedex 20


Procedure for Identification and Characterization of Drugs Efficient Against Mammalian Prion: From a Yeast-Based Antiprion Drug Screening Assay to In Vivo Mouse Models

Author(s): Cecile Voisset, Sven J. Saupe, Herve Galons and Marc Blondel

Affiliation: INSERM U613, Faculte de Medecine et des Sciences de la Sante, 22 Avenue Camille Desmoulins, Brest, F-29200, France.


Prion diseases are fatal and incurable infectious neurodegenerative disorders affecting humans and other mammals. Prions are composed essentially if not solely of PrPSc, a misfolded form of the host-encoded PrP protein. PrPSc catalyzes the transconformation of the normal endogenous PrP (PrPC) into more PrPSc. Prion replication thus corresponds to the propagation of an altered folding state of PrP. Several prion proteins have also been identified in the simple model organism Saccharomyces cerevisiae. Yeast prion-based screening assays have allowed identification of drugs active against mammalian prions, thus revealing the existence of common prion propagation mechanisms conserved from yeast to human. To identify these conserved targets, antiprion compounds isolated in yeast can be used as baits in reverse screening strategies. Once identified, these targets could in turn lead to the development of mechanism-based cell-free antiprion screening assays. A reverse screening procedure has been performed for 6AP and GA, two antiprion compounds isolated using a yeast-based assay. Protein folding activity of the large ribosomal RNA was found to be a physical and a functional target of both 6AP and GA therefore suggesting that this activity of the ribosome may constitute a novel mechanism involved in prion propagation and, as a consequence, a new screening target.

Keywords: Mammalian Prion, Antiprion Drug Screening, Mouse Models, Saccharomyces cerevisiae, ribosomal RNA

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Article Details

Page: [31 - 39]
Pages: 9
DOI: 10.2174/1871526510909010031