Prion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrP) of the cellular prion protein (PrP) in the brain. Two types of cellular prion (PrP) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrP, whereas Accelerators favour the formation of PrP. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrP molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg and Glu/Glu. Computational docking data indicate that the hydrophobic benzamide group of the EB, GFP23 and the 1-(3,3-dimethylcyclohexylidene)piperidinium group of the ACC, GFP22 play an important role in inhibition and conversion from SHaPrP to SHaPrP, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrP. Consistent with its role as an ACC, titration of GFP22 resulted in widespread chemical shift changes and signal intensity loss due to protein unfolding. Virtual screening of a ligand database using the molecular scaffold developed from the set of EBs identified six of our compounds (previously studied using fluorescence quenching) as being among the top 100 best binders. Among them, compounds 5 and 6 were found to be particularly potent in decreasing the accumulation SHaPrP in ScN2a cells with an IC of ∼35µM and 20µM.
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http://dx.doi.org/10.1016/j.bmc.2017.09.024 | DOI Listing |
Sci Rep
December 2024
Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
PrPc is expressed in various tumors and is associated with cancer progression, but previous studies have shown conflicting results regarding its relationship with patient prognosis-potentially due to differences in the antibodies used. This study aimed to clarify the relationship between PrPc expression and primary esophageal squamous cell carcinoma (ESCC) and primary hepatocellular carcinoma (HCC) using a novel anti-PrPc antibody, 4AA-m, noted for its high specificity and sensitivity. We used flow cytometry to detect PrPc expression in ESCC and HCC cell lines.
View Article and Find Full Text PDFFront Mol Neurosci
December 2024
Laboratory of Veterinary Hygiene, Faculty of Veterinary Medicine, Graduate School of Infectious Diseases, Hokkaido University, Sapporo, Japan.
The accumulation of a disease-specific isoform of prion protein (PrP) and histopathological lesions, such as neuronal loss, are unevenly distributed in the brains of humans and animals affected with prion diseases. This distribution varies depending on the diseases and/or the combinations of prion strain and experimental animal. The brain region-dependent distribution of PrP and neuropathological lesions suggests a neuronal cell-type-dependent prion propagation and vulnerability to prion infection.
View Article and Find Full Text PDFACS Chem Neurosci
December 2024
Department of Chemistry, Center for Research and Advanced Studies (Cinvestav), Mexico City 07360, Mexico.
Alzheimer's disease (AD) is the most common form of dementia worldwide. AD brains are characterized by the accumulation of amyloid-β peptides (Aβ) that bind Cu and have been associated with several neurotoxic mechanisms. Although the use of copper chelators to prevent the formation of Cu-Aβ complexes has been proposed as a therapeutic strategy, recent studies show that copper is an important neuromodulator that is essential for a neuroprotective mechanism mediated by Cu binding to the cellular prion protein (PrP).
View Article and Find Full Text PDFImmunol Cell Biol
December 2024
Cellular and Molecular Medicine Research Institute, Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran.
Neurodegeneration and neuroinflammation disorders are mainly the result of the deposition of various proteins, such as α-synuclein, amyloid-β and prions, which lead to the initiation and activation of inflammatory responses. Different chemokines are involved in the infiltration and movement of inflammatory leukocytes into the central nervous system (CNS) that express chemokine receptors. Dysregulation of several members of chemokines has been shown in the CNS, cerebrospinal fluid and peripheral blood of patients who have neurodegenerative disorders.
View Article and Find Full Text PDFVet Immunol Immunopathol
December 2024
Infectious Bacterial Diseases Research Unit, National Animal Disease Center, Agricultural Research Service, United States Department of Agriculture, Ames, IA, USA.
Identifying cellular markers within archived formalin-fixed, paraffin-embedded (FFPE) tissues is critical for understanding tissue landscapes impacting animal health, but in situ detection methods are limited in veterinary species by a restricted toolbox of species-compatible immunoreagents. We identify antibodies with conserved in situ reactivity to IBA-1 (macrophages/dendritic cells), CD3ε (T cells), Pax5 (B cells), Ki-67 (cycling cells), and cytokeratin type I/II (epithelial cells) in FFPE tissues of pigs, cattle, and white-tailed deer. Multiplexed brightfield detection (IBA-1/CD3ε/Pax5) in lymph nodes of all three species demonstrated species-specific and species-conserved features of cellular architecture.
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