Chemical-Mediated Targeted Protein Degradation in Neurodegenerative Diseases

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.

Protein clearance strategies for disease intervention

“…As ongoing therapies and clinical trials for cancer have been discussed in previous sections, here we will focus on interventions that could alleviate neurodegenerative diseases. The disparities between the pathophysiology of distinct proteinopathies led to exploring many different types of interventions for preventing protein aggregation (Arosio et al 2014 ; Hyun and Shin 2021 ; Lashuel 2021 ; Salahuddin et al 2021 ). Such interventions can be classified as antibodies, protein stabilizers, nanoparticles, sequestering monomers and small molecule inhibitors of aggregation.…”

Challenges in Discovering Drugs That Target the Protein–Protein Interactions of Disordered Proteins

“…In this context, important progress has been made by adapting the UPS so as to target selected substrates and prevent PPIs [68]. A chimeric compound of E3 ubiquitin ligase and a SYN-binding motif may allow PD to be treated (Figure 5) [69]. This approach has been used to eliminate over-expressed SYN [70,71].…”

Multifaceted targeted protein degradation systems for different cellular compartments

“…Below we give an overview of the ways PROTACs have recently been applied to Parkinson's disease. 7,8 Parkinson's disease (PD) is a neurological disorder, whose pathological signatures are the degeneration of dopamine neurons and the formation of alpha-synuclein-enriched Lewy bodies. 9 Genetic studies of familial PD cases have identified mutations, duplications and triplications of α-synuclein and other risk loci.…”

“…The field of PROTACs has evolved rapidly in recent years, encompassing numerous applications to neurodegeneration as well as other human diseases. Below we give an overview of the ways PROTACs have recently been applied to Parkinson's disease 7,8 …”