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Pharmacological Agents Targeting the Cellular Prion Protein
Prion diseases are associated with the conversion of the cellular prion protein (PrP(C)), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP(Sc)) that accumulates in brain tissues of affected individuals. PrP(Sc) is a...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874753/ https://www.ncbi.nlm.nih.gov/pubmed/29518975 http://dx.doi.org/10.3390/pathogens7010027 |
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author | Barreca, Maria Letizia Iraci, Nunzio Biggi, Silvia Cecchetti, Violetta Biasini, Emiliano |
author_facet | Barreca, Maria Letizia Iraci, Nunzio Biggi, Silvia Cecchetti, Violetta Biasini, Emiliano |
author_sort | Barreca, Maria Letizia |
collection | PubMed |
description | Prion diseases are associated with the conversion of the cellular prion protein (PrP(C)), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP(Sc)) that accumulates in brain tissues of affected individuals. PrP(Sc) is a self-catalytic protein assembly capable of recruiting native conformers of PrP(C), and causing their rearrangement into new PrP(Sc) molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrP(Sc), and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrP(Sc) might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrP(C), the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrP(C) in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrP(C), discussing pharmacological properties and therapeutic potentials of each chemical class. |
format | Online Article Text |
id | pubmed-5874753 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-58747532018-04-02 Pharmacological Agents Targeting the Cellular Prion Protein Barreca, Maria Letizia Iraci, Nunzio Biggi, Silvia Cecchetti, Violetta Biasini, Emiliano Pathogens Review Prion diseases are associated with the conversion of the cellular prion protein (PrP(C)), a glycoprotein expressed at the surface of a wide variety of cell types, into a misfolded conformer (the scrapie form of PrP, or PrP(Sc)) that accumulates in brain tissues of affected individuals. PrP(Sc) is a self-catalytic protein assembly capable of recruiting native conformers of PrP(C), and causing their rearrangement into new PrP(Sc) molecules. Several previous attempts to identify therapeutic agents against prion diseases have targeted PrP(Sc), and a number of compounds have shown potent anti-prion effects in experimental models. Unfortunately, so far, none of these molecules has successfully been translated into effective therapies for prion diseases. Moreover, mounting evidence suggests that PrP(Sc) might be a difficult pharmacological target because of its poorly defined structure, heterogeneous composition, and ability to generate different structural conformers (known as prion strains) that can elude pharmacological intervention. In the last decade, a less intuitive strategy to overcome all these problems has emerged: targeting PrP(C), the common substrate of any prion strain replication. This alternative approach possesses several technical and theoretical advantages, including the possibility of providing therapeutic effects also for other neurodegenerative disorders, based on recent observations indicating a role for PrP(C) in delivering neurotoxic signals of different misfolded proteins. Here, we provide an overview of compounds claimed to exert anti-prion effects by directly binding to PrP(C), discussing pharmacological properties and therapeutic potentials of each chemical class. MDPI 2018-03-07 /pmc/articles/PMC5874753/ /pubmed/29518975 http://dx.doi.org/10.3390/pathogens7010027 Text en © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Barreca, Maria Letizia Iraci, Nunzio Biggi, Silvia Cecchetti, Violetta Biasini, Emiliano Pharmacological Agents Targeting the Cellular Prion Protein |
title | Pharmacological Agents Targeting the Cellular Prion Protein |
title_full | Pharmacological Agents Targeting the Cellular Prion Protein |
title_fullStr | Pharmacological Agents Targeting the Cellular Prion Protein |
title_full_unstemmed | Pharmacological Agents Targeting the Cellular Prion Protein |
title_short | Pharmacological Agents Targeting the Cellular Prion Protein |
title_sort | pharmacological agents targeting the cellular prion protein |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874753/ https://www.ncbi.nlm.nih.gov/pubmed/29518975 http://dx.doi.org/10.3390/pathogens7010027 |
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