New inhibitors of prion replication that target the amyloid precursor.
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.
Charvériat
Mathieu
M
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
Reboul
Marlène
M
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
Wang
Qian
Q
Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
Picoli
Christèle
C
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
Lenuzza
Natacha
N
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
Montagnac
Alain
A
Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
Nhiri
Naima
N
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.
Jacquet
Eric
E
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.
Guéritte
Françoise
F
Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
Lallemand
Jean-Yves
JY
Institut de Chimie des Substances Naturelles, CNRS, 1 avenue de la Terrasse, F-91198 Gif-sur-Yvette Cedex, France.
Deslys
Jean-Philippe
JP
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
Mouthon
Franck
F
Institute of Emerging Diseases and Innovative Therapies, CEA, F-92265 Fontenay-aux-Roses, France.
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
D016564:Amyloid beta-Protein Precursor; D011328:Prions; D054852:Small Molecule Libraries