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Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases
Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the mai...
Autores principales: | , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305580/ https://www.ncbi.nlm.nih.gov/pubmed/34202541 http://dx.doi.org/10.3390/life11070607 |
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author | Hyun, Soonsil Shin, Dongyun |
author_facet | Hyun, Soonsil Shin, Dongyun |
author_sort | Hyun, Soonsil |
collection | PubMed |
description | Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases. |
format | Online Article Text |
id | pubmed-8305580 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-83055802021-07-25 Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases Hyun, Soonsil Shin, Dongyun Life (Basel) Review Neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, are a class of diseases that lead to dysfunction of cognition and mobility. Aggregates of misfolded proteins such as β-amyloid, tau, α-synuclein, and polyglutamates are known to be among the main causes of neurodegenerative diseases; however, they are considered to be some of the most challenging drug targets because they cannot be modulated by conventional small-molecule agents. Recently, the degradation of target proteins by small molecules has emerged as a new therapeutic modality and has garnered the interest of the researchers in the pharmaceutical industry. Bifunctional molecules that recruit target proteins to a cellular protein degradation machinery, such as the ubiquitin–proteasome system and autophagy–lysosome pathway, have been designed. The representative targeted protein degradation technologies include molecular glues, proteolysis-targeting chimeras, hydrophobic tagging, autophagy-targeting chimeras, and autophagosome-tethering compounds. Although these modalities have been shown to degrade many disease-related proteins, such technologies are expected to be potentially important for neurogenerative diseases caused by protein aggregation. Herein, we review the recent progress in chemical-mediated targeted protein degradation toward the discovery of drugs for neurogenerative diseases. MDPI 2021-06-24 /pmc/articles/PMC8305580/ /pubmed/34202541 http://dx.doi.org/10.3390/life11070607 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Review Hyun, Soonsil Shin, Dongyun Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title | Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title_full | Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title_fullStr | Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title_full_unstemmed | Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title_short | Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases |
title_sort | chemical-mediated targeted protein degradation in neurodegenerative diseases |
topic | Review |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305580/ https://www.ncbi.nlm.nih.gov/pubmed/34202541 http://dx.doi.org/10.3390/life11070607 |
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