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Originally published as JGV in Press, 10.1099/vir.0.009084-0 on March 4, 2009 J Gen Virol 90 (2009), 1294-1301; DOI 10.1099/vir.0.009084-0

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New inhibitors of prion replication that target the amyloid precursor

Mathieu Charvériat1, Marlène Reboul1, Qian Wang2, Christèle Picoli1, Natacha Lenuzza1, Alain Montagnac2, Naima Nhiri2,3, Eric Jacquet2,3, Françoise Guéritte2, Jean-Yves Lallemand2, Jean-Philippe Deslys1 and Franck Mouthon1

1 Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France
2 Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France
3 IMAGIF-CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France

Correspondence
Jean-Philippe Deslys
jean-philippe.deslys{at}cea.fr

At present, there is 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 2960 natural and synthetic compounds in two cell lines chronically infected with mouse prions, and have identified eight new inhibitors of prion replication in vitro. They belong to two distinct chemical families that have not previously been recognised as effective 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 cellular prion protein metabolism. Furthermore, using a quantitative approach for the study of protein stability, it was shown that the erythromycin A derivative altered prion protein 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 to define new molecules that are active against prion diseases.

Two supplementary figures are available with the online version of this paper.






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