ArticleProceedings of the National Academy of Sciences of the United States of America2007
Hot spots in prion protein for pathogenic conversion.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 178 citations in OpenAlex.
- Aberrant assembly of RNA recognition motif 1 links to pathogenic conversion of TAR DNA-binding protein of 43 kDa (TDP-43).The Journal of biological chemistry · 2013Trial
- Prion propagation is controlled by discrete structural regions of PrP rather than overall stability.The Journal of biological chemistry · 2026Article
- Novel anti-prion compounds screening in prion-infected cell culture model combined with surface plasmon resonance analysis.Scientific reports · 2025Article
- Exploring immunotherapeutic strategies for neurodegenerative diseases: a focus on Huntington's disease and Prion diseases.Acta pharmacologica Sinica · 2025Review
- Therapeutic Trajectories in Human Prion Diseases.Sub-cellular biochemistry · 2025Review
- Adaptation of the protein misfolding cyclic amplification (PMCA) technique for the screening of anti-prion compounds.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2024Article
- Fluorimetric Detection of Insulin Misfolding by Probes Derived from Functionalized Fluorene Frameworks.Molecules (Basel, Switzerland) · 2024Article
- Synthesis and anti-prion aggregation activity of acylthiosemicarbazide analogues.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Therapeutic strategies for identifying small molecules against prion diseases.Cell and tissue research · 2023Review
- Prion therapeutics: Lessons from the past.Prion · 2022Review
- Innovative Non-PrP-Targeted Drug Strategy Designed to Enhance Prion Clearance.Journal of medicinal chemistry · 2022Article
- Melatonin: Regulation of Prion Protein Phase Separation in Cancer Multidrug Resistance.Molecules (Basel, Switzerland) · 2022Review
- Combination of structure-based virtual screening, molecular docking and molecular dynamics approaches for the discovery of anti-prion fibril flavonoids.Frontiers in molecular biosciences · 2022Article
- Hampering the early aggregation of PrP-E200K protein by charge-based inhibitors: a computational study.Journal of computer-aided molecular design · 2021Article
- Methionine oxidation within the prion protein.Prion · 2020Review
- Article
- Natural and Synthetic Derivatives of Hydroxycinnamic Acid Modulating the Pathological Transformation of Amyloidogenic Proteins.Molecules (Basel, Switzerland) · 2020Review
- Novel Compounds Identified by Structure-Based Prion Disease Drug Discovery Using In Silico Screening Delay the Progression of an Illness in Prion-Infected Mice.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2020Article
- BMD42-2910, a Novel Benzoxazole Derivative, Shows a Potent Anti-prion Activity and Prolongs the Mean Survival in an Animal Model of Prion Disease.Experimental neurobiology · 2020Article
- Direct interaction of DNMT inhibitors to PrPActa pharmaceutica Sinica. B · 2019Article
6 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.