title: New inhibitors of prion replication that target the amyloid precursor.
abstract: 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.
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Charvériat
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Reboul
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Picoli
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Natacha
authors.initials: N
authors.lastname: Lenuzza
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Montagnac
authors.affiliation: IMAGIF-CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.|Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Naima
authors.initials: N
authors.lastname: Nhiri
authors.affiliation: IMAGIF-CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.|Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Jacquet
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Guéritte
authors.affiliation: Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Lallemand
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Deslys
authors.affiliation: Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Mouthon
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors*; D000818:Animals; D001681:Biological Assay / Q000379:methods; D002460:Cell Line; D051379:Mice; D011328:Prions / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D054852:Small Molecule Libraries
chemical_list: D016564:Amyloid beta-Protein Precursor; D011328:Prions; D054852:Small Molecule Libraries