ST1859 reduces prion infectivity and increase survival in experimental scrapie.
On the basis of the structural homologies between ST1859 (1[(2-hydroxy-1-naphtyl)methyl]-2-naphthol) and the anti-prion agents and its anti-amyloidogenic activity, we tested whether this molecule altered the biochemical properties of aggregates formed in vitro by synthetic prion peptides and affected prion infectivity in experimental scrapie. Co-incubation of ST1859 with the peptides PrP 106-126 and PrP 82-146 reduced their fibrillogenic capacity and their resistance to digestion with protease K. Hamsters inoculated with the ST1859-treated homogenate showed a significant delay in the onset of clinical signs of disease and longer survival. Survival was also significantly longer in infected hamsters treated peripherally with ST1859 for the whole post-inoculation period until the onset of clinical symptoms. Similar results were found with the analogue ST1745. Our data indicate that ST1859 reduces prion infectivity and can exert a therapeutic effect in experimental scrapie.
Colombo
Laura
L
Istituto di Ricerche Farmacologiche Mario Negri, Via G. La Masa 19, Milan, Italy.
Piovesan
Paola
P
Ghirardi
Orlando
O
Salmona
Mario
M
Forloni
Gianluigi
G
D000818:Animals; D006224:Cricetinae; D019286:Endopeptidase K / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008647:Mesocricetus; D009284:Naphthols / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D018622:PrP 27-30 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012608:Scrapie / Q000188:drug therapy*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use
C544732:1,1-methylene-di-(2-naphthol)-3-acetyloxy-4-trimethylammonio-butanoate; D009284:Naphthols; D018622:PrP 27-30 Protein; C010635:1,1'-methylenedi-2-naphthol; D005680:gamma-Aminobutyric Acid; D019286:Endopeptidase K