Recent advances of PROTACs technology in neurodegenerative diseases

Abstract

Neurodegenerative diseases, like Alzheimer's disease, Huntington's disease, Parkinson's disease, progressive supranuclear palsy, and frontotemporal dementia are among the refractory diseases that lack appropriate drugs and treatments. Numerous disease-causing proteins in neurodegenerative diseases are undruggable for traditional drugs. Many clinical studies of drugs for Alzheimer's disease have failed, and none of the substances that slowed the amyloid-β (Aβ) accumulation process have been approved for use in clinical trials. A novel approach to addressing this issue is Proteolysis targeting chimeras (PROTACs) technology. PROTACs are heterogeneous functional molecules joined by a chemical linker and include binding ligands for the target protein and recruitment ligands for the E3 ligand. When a PROTAC binds to a target protein, the E3 ligand enzyme is brought into close contact and the target protein begins to be polyubiquitinated, followed by proteasome-mediated degradation. Numerous neurodegenerative disease-related targets, including α-Synuclein, mHTT, GSK-3, LRRK2, Tau, TRKA, and TRKC have been successfully targeted by PROTACs to date. This article presents a comprehensive overview of the development of PROTACs in neurodegenerative diseases. These PROTACs' chemical structures, preparative routes, in vitro and in vivo activities, and pharmacodynamics are outlined. We also offer our viewpoint on PROTACs' probable challenges and future prospects.