title: Hot spots in prion protein for pathogenic conversion.
abstract: 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.
authors.affiliation: 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
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kuwata
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Nishida
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yuji O
authors.initials: YO
authors.lastname: Kamatari
authors.forename: Junji
authors.initials: J
authors.lastname: Hosokawa-Muto
authors.forename: Kota
authors.initials: K
authors.lastname: Kodama
authors.forename: Hironori K
authors.initials: HK
authors.lastname: Nakamura
authors.forename: Kiminori
authors.initials: K
authors.lastname: Kimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Yuka
authors.initials: Y
authors.lastname: Takakura
authors.forename: Susumu
authors.initials: S
authors.lastname: Shirabe
authors.forename: Jiro
authors.initials: J
authors.lastname: Takata
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Kataoka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Katamine
mesh_terms: 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
chemical_list: D000081:Acetamides; D018621:PrPC Proteins; D011994:Recombinant Proteins