Screening a library of potential prion therapeutics against cellular prion proteins and insights into their mode of biological activities by surface plasmon resonance

Touil, Faiza; Pratt, Steve D.; Mutter, Roger; Chen, Beining

doi:10.1016/j.jpba.2005.08.011

Cited by 37 publications

(40 citation statements)

References 53 publications

(65 reference statements)

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“…Binding of GN8 to PrP C was confirmed by the surface plasmon resonance (21), and its dissociation constant was estimated to be 3.9 Ϯ 0.2 ϫ 10 Ϫ6 M from the Scatchard plot ( Fig. 2a; see also SI Fig.…”

Section: Resultsmentioning

confidence: 91%

Hot spots in prion protein for pathogenic conversion

Kuwata

Nishida

Matsumoto

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

221

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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.anti-prion compound ͉ binding sites ͉ chemical chaperone ͉ dynamicsbased drug discovery ͉ transmissible spongiform encephalopathy

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Section: Resultsmentioning

confidence: 91%

Hot spots in prion protein for pathogenic conversion

Kuwata

Nishida

Matsumoto

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

173

221

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“…The usefulness of this method in screening for PrP binding ligands is also reported very recently by other researchers. 29) Two chemicals, ThT and diazepam, showed high binding response but did not inhibit PrPres formation within a nontoxic dose range. Of them, ThT exhibited very low or no affinity with PrP121-231 but the next highest binding response to QC.…”

Section: Discussionmentioning

confidence: 95%

Surface Plasmon Resonance Analysis for the Screening of Anti-prion Compounds

Kawatake

Nishimura

Sakaguchi

et al. 2006

Biological & Pharmaceutical Bulletin

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“…A 4000 -5000 RU immobilization level was obtained. For binding measurements P30, A12, A15, and the positive control quinacrine (Touil et al, 2006) were injected at 40 M in PBS containing 5% DMSO with a flow rate of 30 l/min in PrP and blank flow cells. Surfaces were then washed with pulses of 10 mM NaOH until complete regeneration.…”

Section: Ethics Statement the Comité Régional D'ethique De Montpellimentioning

confidence: 99%

Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity

Ayrolles-Torro¹,

Imberdis²,

Torrent³

et al. 2011

J. Neurosci.

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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.

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Screening a library of potential prion therapeutics against cellular prion proteins and insights into their mode of biological activities by surface plasmon resonance

Cited by 37 publications

References 53 publications

Hot spots in prion protein for pathogenic conversion

Hot spots in prion protein for pathogenic conversion

Surface Plasmon Resonance Analysis for the Screening of Anti-prion Compounds

Oligomeric-Induced Activity by Thienyl Pyrimidine Compounds Traps Prion Infectivity

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