Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases
- Authors
- Hyun, Soonsil; Shin, Dongyun
- Issue Date
- Jul-2021
- Publisher
- MDPI
- Keywords
- Autophagy; Drug design; Neurodegenerative disease; Protac; Protein degradation; Soonsil Hyun and Dongyun Shin; Ubiquitin-proteasome system
- Citation
- LIFE-BASEL, v.11, no.7
- Journal Title
- LIFE-BASEL
- Volume
- 11
- Number
- 7
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/81779
- DOI
- 10.3390/life11070607
- ISSN
- 0024-3019
- Abstract
- 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. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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