Hot spots in prion protein for pathogenic conversion.
Prion proteins are key molecules in transmissible spongiform encephalopathies (TSEs), but the precise mechanism of the conversion from the cellular form (PrP(C)) to the scrapie form (PrP(Sc)) is still unknown. Here we discovered a chemical chaperone to stabilize the PrP(C) conformation and identified the hot spots to stop the pathogenic conversion. We conducted in silico screening to find compounds that fitted into a "pocket" created by residues undergoing the conformational rearrangements between the native and the sparsely populated high-energy states (PrP*) and that directly bind to those residues. Forty-four selected compounds were tested in a TSE-infected cell culture model, among which one, 2-pyrrolidin-1-yl-N-[4-[4-(2-pyrrolidin-1-yl-acetylamino)-benzyl]-phenyl]-acetamide, termed GN8, efficiently reduced PrP(Sc). Subsequently, administration of GN8 was found to prolong the survival of TSE-infected mice. Heteronuclear NMR and computer simulation showed that the specific binding sites are the A-S2 loop (N159) and the region from helix B (V189, T192, and K194) to B-C loop (E196), indicating that the intercalation of these distant regions (hot spots) hampers the pathogenic conversion process. Dynamics-based drug discovery strategy, demonstrated here focusing on the hot spots of PrP(C), will open the way to the development of novel anti-prion drugs.
Kuwata
Kazuo
K
Center for Emerging Infectious Diseases, Department of Gene and Development, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan. kuwata@gifu-u.ac.jp
Nishida
Noriyuki
N
Matsumoto
Tomoharu
T
Kamatari
Yuji O
YO
Hosokawa-Muto
Junji
J
Kodama
Kota
K
Nakamura
Hironori K
HK
Kimura
Kiminori
K
Kawasaki
Makoto
M
Takakura
Yuka
Y
Shirabe
Susumu
S
Takata
Jiro
J
Kataoka
Yasufumi
Y
Katamine
Shigeru
S
D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D019295:Computational Biology; D051379:Mice; D018621:PrPC Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000472:pathogenicity*; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000378:metabolism
D000081:Acetamides; D018621:PrPC Proteins; D011994:Recombinant Proteins