Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/31758
Title: A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location
Authors: Ferreira, N. C.
Ascari, L. M.
Hughson, A. G.
Cavalheiro, G. R.
Góes, C. F.
Fernandes, P. N.
Hollister, J. R.
Conceição, R. A. da
Silva, D. S.
Souza, A. M. T.
Barbosa, M. L. C.
Lara, F. A.
Martins, R. A. P.
Caughey, B.
Cordeiro, Y.
Affilliation: Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Laboratory of Persistent Viral Diseases. Rocky Mountain Laboratories. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Hamilton, Montana, USA.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Laboratory of Persistent Viral Diseases. Rocky Mountain Laboratories. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Hamilton, Montana, USA.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ. Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Microbiologia Celular. Rio de Janeiro, RJ. Brasil.
Universidade Federal do Rio de Janeiro. Instituto de Ciências Biomédicas. Rio de Janeiro, RJ, Brasil.
Laboratory of Persistent Viral Diseases. Rocky Mountain Laboratories. National Institute of Allergy and Infectious Diseases. National Institutes of Health. Hamilton, Montana, USA.
Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. Rio de Janeiro, RJ, Brasil.
Abstract: The search for antiprion compounds has been encouraged by the fact that transmissible spongiform encephalopathies (TSEs) share molecular mechanisms with more prevalent neurodegenerative pathologies, such as Parkinson's and Alzheimer's diseases. Cellular prion protein (PrPC) conversion into protease-resistant forms (protease-resistant PrP [PrPRes] or the scrapie form of PrP [PrPSc]) is a critical step in the development of TSEs and is thus one of the main targets in the screening for antiprion compounds. In this work, three trimethoxychalcones (compounds J1, J8, and J20) and one oxadiazole (compound Y17), previously identified in vitro to be potential antiprion compounds, were evaluated through different approaches in order to gain inferences about their mechanisms of action. None of them changed PrPC mRNA levels in N2a cells, as shown by reverse transcription-quantitative real-time PCR. Among them, J8 and Y17 were effective in real-time quaking-induced conversion reactions using rodent recombinant PrP (rPrP) from residues 23 to 231 (rPrP23-231) as the substrate and PrPSc seeds from hamster and human brain. However, when rPrP from residues 90 to 231 (rPrP90-231), which lacks the N-terminal domain, was used as the substrate, only J8 remained effective, indicating that this region is important for Y17 activity, while J8 seems to interact with the PrPC globular domain. J8 also reduced the fibrillation of mouse rPrP23-231 seeded with in vitro-produced fibrils. Furthermore, most of the compounds decreased the amount of PrPC on the N2a cell surface by trapping this protein in the endoplasmic reticulum. On the basis of these results, we hypothesize that J8, a nontoxic compound previously shown to be a promising antiprion agent, may act by different mechanisms, since its efficacy is attributable not only to PrP conversion inhibition but also to a reduction of the PrPC content on the cell surface.
Keywords: Prion protein
Therapy
Antiscrapie compounds
RT-QuIC
Prion strains
Antiprion
Antiscrapie
Prions
PrP
keywords: Proteínas Priônicas
Terapia
Príons
Compostos antiscrapie
Estirpes de priões
Issue Date: 2018
Publisher: American Society for Microbiology
Citation: FERREIRA, N. C. et al. A Promising Antiprion Trimethoxychalcone Binds to the Globular Domain of the Cellular Prion Protein and Changes Its Cellular Location. Antimicrobial Agents and Chemmotherapy, v. 62, n. 2, p. 1-17, Feb. 2018.
DOI: 10.1128/AAC.01441-17
ISSN: 0066-4804
Copyright: restricted access
Appears in Collections:IOC - Artigos de Periódicos

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