Oligomeric-induced activity by thienyl pyrimidine compounds traps prion infectivity.
Accumulation of PrP(Sc), an abnormal form of cellular prion protein (PrP), in the brain of animals and humans leads to fatal neurodegenerative disorders known as prion diseases. Limited protease digestion of PrP(Sc) produces a truncated form called PrP(27-30) that retains prion infectivity and is the main marker of disease targeted in most diagnostic tests. In the search for new anti-prion molecules, drug-screening assays on prion-infected murine cells have been oriented toward decreasing levels of PrP(27-30). In contrast, we screened for drugs promoting multimers of PrP(27-30), illustrating a possible stabilization of mouse PrP(Sc) species, because recent studies aiming to characterize the conformational stability of various prion strains showed that stable recombinant amyloids produced more stable prion strain, leading to longest incubation time. We identified a family of thienyl pyrimidine derivatives that induce SDS-resistant dimers and trimers of PrP(27-30). Bioassays performed on mice brain homogenates treated with these compounds showed that these thienyl pyrimidine derivatives diminished prion infectivity in vivo. Oligomeric-induced activity by thienyl pyrimidine compounds is a promising approach not only to understanding the pathogenesis of prions but also for prion diagnostics. This approach could be extended to other neurodegenerative "prionopathies," such as Alzheimer's, Huntington, or Parkinson's diseases.
Université Montpellier 2, Montpellier, F-34095 France.
Adeline
A
Ayrolles-Torro
Thibaut
T
Imberdis
Joan
J
Torrent
Karine
K
Toupet
Ilia V
IV
Baskakov
Guillaume
G
Poncet-Montange
Catherine
C
Grégoire
Françoise
F
Roquet-Baneres
Sylvain
S
Lehmann
Didier
D
Rognan
Martine
M
Pugnière
Jean-Michel
JM
Verdier
Véronique
V
Perrier
D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D019286:Endopeptidase K / Q000494:pharmacology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009447:Neuroblastoma / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D018621:PrPC Proteins / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D017096:Prion Diseases / Q000188:drug therapy / Q000473:pathology*; D011487:Protein Conformation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D012825:Silicon; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection / Q000379:methods
D000813:Anilides; D005904:Glial Fibrillary Acidic Protein; D010446:Peptide Fragments; D018621:PrPC Proteins; D011743:Pyrimidines; C071763:2-(methylthio)benzanilide; D010447:Peptide Hydrolases; D019286:Endopeptidase K; D012825:Silicon