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Published online ahead of print on 4 March 2009 as doi:10.1099/vir.0.009084-0
Journal of General Virology 2009;90:1294.

A more recent version of this article appeared on May 1, 2009 J Gen Virol (2009), DOI 10.1099/vir.0.009084-0
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New inhibitors of Prion replication that target amyloid precursor

Mathieu Charvériat1, Marlène Reboul1, Qian Wang2, Christèle Picoli1, Natacha Lenuzza1, Alain Montagnac2, Naima Nhiri3, Eric Jacquet3, Françoise Guéritte2, Jean-Yves Lallemand2, Jean-Philippe Deslys1,4 and Franck Mouthon1

1 Institute of Emerging Diseases and Innovative Therapies, CEA;
2 Institut de Chimie des Substances Naturelles, CNRS;
3 IMAGIF-CNRS

4 E-mail: jean-philippe.deslys{at}cea.fr

There is at present no effective therapy for any of the neurodegenerative amyloidoses, despite renewed efforts to identify compounds active against the various implicated pathogenetic molecules. We have screened a library of 2,960 natural and synthetic compounds in two cell lines chronically infected by mouse Prions, and have identified eight new in vitro inhibitors of Prion replication. They belong to two distinct chemical families, previously unknown in the field of Transmissible Spongiform Encephalopathies: seven are 3-aminosteroids, and one is a derivative of erythromycin A with an oxime functionality. Our results suggest that these aminosteroids inhibit Prion replication by triggering a common target, possibly implicated in the regulatory pathways of PrPc metabolism. Furthermore, using a quantitative approach for the study of protein stability, it was shown that the erythromycin A derivative altered PrP stability, by direct interaction. Such direct targeting of this amyloid precursor might provide new clues for the understanding of Prion diseases, and more importantly help define new active molecules against Prion diseases.

Received 9 December 2008; accepted 2 February 2009.




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