Interactions of recombinant prions with compounds of therapeutical significance.
The transformation of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is implicated in the invariably fatal transmissible spongiform encephalopathies. To identify a mechanism to prevent the undesired PrP(C)-->PrP(Sc) transformation, we investigated the interactions of recombinant prion proteins with a number of potential therapeutic agents which inhibit the PrP(Sc) formation, infectivity, and the accumulation of the misfolded form. We show that the prion aggregates formed in the presence of six compounds have no beta-structure, which is typical of the infectious form, and possess considerably higher alpha-helical content than the normal PrP(C). The investigated compounds stimulate the formation of alpha-helices and the destruction of beta-structure. They prevent the transformation of alpha-helical structure into beta-sheets. Probably, this is the reason for the resistance to PrP(C)-->PrP(Sc) transformation in the presence of these compounds. The results may be useful for the future therapy of neurodegenerative diseases.
Georgieva
Dessislava
D
University of Hamburg, Department of Biochemistry and Molecular Biology, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
Schwark
Daniel
D
von Bergen
Martin
M
Redecke
Lars
L
Genov
Nicolay
N
Betzel
Christian
C
D001665:Binding Sites; D004318:Doxycycline / Q000031:analogs & derivatives* / Q000737:chemistry; D008744:Methylamines / Q000737:chemistry*; D011328:Prions / Q000032:analysis / Q000737:chemistry* / Q000235:genetics; D011395:Promazine / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D011489:Protein Denaturation; D011796:Quinacrine / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry; D013752:Tetracycline / Q000737:chemistry*
D008744:Methylamines; D011328:Prions; D011804:Quinolines; D011994:Recombinant Proteins; D013752:Tetracycline; D011796:Quinacrine; C023336:trimethylamine; D004318:Doxycycline; D011395:Promazine