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Prion therapeutics: Lessons from the past

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP(C)) into scrapie isoform (PrP(Sc)) in the Central nervous system (CNS) resulte...

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Autores principales: Shim, Kyu Hwan, Sharma, Niti, An, Seong Soo A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754114/
https://www.ncbi.nlm.nih.gov/pubmed/36515657
http://dx.doi.org/10.1080/19336896.2022.2153551
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author Shim, Kyu Hwan
Sharma, Niti
An, Seong Soo A
author_facet Shim, Kyu Hwan
Sharma, Niti
An, Seong Soo A
author_sort Shim, Kyu Hwan
collection PubMed
description Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP(C)) into scrapie isoform (PrP(Sc)) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP(C) to PrP(Sc) conversion, increasing PrP(Sc) removal, and PrP(C) stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.
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spelling pubmed-97541142023-02-06 Prion therapeutics: Lessons from the past Shim, Kyu Hwan Sharma, Niti An, Seong Soo A Prion Review Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP(C)) into scrapie isoform (PrP(Sc)) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP(C) to PrP(Sc) conversion, increasing PrP(Sc) removal, and PrP(C) stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro, only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases. Taylor & Francis 2022-12-14 /pmc/articles/PMC9754114/ /pubmed/36515657 http://dx.doi.org/10.1080/19336896.2022.2153551 Text en © 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Review
Shim, Kyu Hwan
Sharma, Niti
An, Seong Soo A
Prion therapeutics: Lessons from the past
title Prion therapeutics: Lessons from the past
title_full Prion therapeutics: Lessons from the past
title_fullStr Prion therapeutics: Lessons from the past
title_full_unstemmed Prion therapeutics: Lessons from the past
title_short Prion therapeutics: Lessons from the past
title_sort prion therapeutics: lessons from the past
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9754114/
https://www.ncbi.nlm.nih.gov/pubmed/36515657
http://dx.doi.org/10.1080/19336896.2022.2153551
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