ArticleBioorganic & medicinal chemistry2014
Novel compounds lowering the cellular isoform of the human prion protein in cultured human cells.
Article in Bioorganic & medicinal chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 25 citations in OpenAlex.
- Phenotypic screening for small molecules that lower PrP in cultured cells.Molecular and cellular neurosciences · 2026Article
- Phenotypic screening for small molecules that lower PrP in cultured cells.bioRxiv : the preprint server for biology · 2026Article
- Recombinant ovine prion protein can be mutated at position 136 to improve its efficacy as an inhibitor of prion propagation.Scientific reports · 2023Article
- The Role of Cellular Prion Protein in Glioma Tumorigenesis Could Be through the Autophagic Mechanisms: A Narrative Review.International journal of molecular sciences · 2023Review
- Identification of a Cardiac Glycoside Exhibiting Favorable Brain Bioavailability and Potency for Reducing Levels of the Cellular Prion Protein.International journal of molecular sciences · 2022Article
- Article
- Novel regulators of PrPC biosynthesis revealed by genome-wide RNA interference.PLoS pathogens · 2021Article
- Antisense oligonucleotides extend survival of prion-infected mice.JCI insight · 2019Article
- Prion protein quantification in human cerebrospinal fluid as a tool for prion disease drug development.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Dual MicroRNA to Cellular Prion Protein Inhibits Propagation of Pathogenic Prion Protein in Cultured Cells.Molecular neurobiology · 2018Article
- Developing Therapeutics for PrP Prion Diseases.Cold Spring Harbor perspectives in medicine · 2017Review
- Identification of Anti-prion Compounds using a Novel Cellular Assay.The Journal of biological chemistry · 2016Article
- Article
- Quantifying prion disease penetrance using large population control cohorts.Science translational medicine · 2016Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
purposePrevious studies showed that lowering PrP(C) concomitantly reduced PrP(Sc) in the brains of mice inoculated with prions. We aimed to develop assays that measure PrP(C) on the surface of human T98G glioblastoma and IMR32 neuroblastoma cells. Using these assays, we sought to identify chemical hits, confirmed hits, and scaffolds that potently lowered PrP(C) levels in human brains cells, without lethality, and that could achieve drug concentrations in the brain after oral or intraperitoneal dosing in mice.
methodsWe utilized HTS ELISA assays to identify small molecules that lower PrP(C) levels by ≥30% on the cell surface of human glioblastoma (T98G) and neuroblastoma (IMR32) cells.
resultsFrom 44,578 diverse chemical compounds tested, 138 hits were identified by single point confirmation (SPC) representing 7 chemical scaffolds in T98G cells, and 114 SPC hits representing 6 scaffolds found in IMR32 cells. When the confirmed SPC hits were combined with structurally related analogs, >300 compounds (representing 6 distinct chemical scaffolds) were tested for dose-response (EC₅₀) in both cell lines, only studies in T98G cells identified compounds that reduced PrP(C) without killing the cells. EC₅₀ values from 32 hits ranged from 65 nM to 4.1 μM. Twenty-eight were evaluated in vivo in pharmacokinetic studies after a single 10 mg/kg oral or intraperitoneal dose in mice. Our results showed brain concentrations as high as 16.2 μM, but only after intraperitoneal dosing.
conclusionsOur studies identified leads for future studies to determine which compounds might lower PrP(C) levels in rodent brain, and provide the basis of a therapeutic for fatal disorders caused by PrP prions.
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Registered trials
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.