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 beta-amyloid, tau, alpha-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.

Automated summary

Neurodegenerative diseases are characterized by dysfunction of cognition and mobility, often caused by aggregates of misfolded proteins. Recently, targeted protein degradation using small molecules has emerged as a promising new therapeutic approach for these challenging diseases. Various technologies, such as molecular glues, have shown success in degrading disease-related proteins and may hold potential for the treatment of neurodegenerative diseases caused by protein aggregation.