The emerging role of proteolysis targeting chimeras (PROTACs) in the treatment of Alzheimer's disease

Proteolysis-targeting technology is a new emerging technique to target mutated, denatured, and misfolded proteins that accumulate in various parts of the body. The accumulation of these aggregated harmful proteins, such as beta-amyloid (A beta), tau, mHTT, polyglutamates, and other proteins in the brain, are some of the reasons for the development of neurodegenerative diseases. A beta accumulation and hyperphosphorylation are the common signals for the progression of Alzheimer's disease (AD). Developing conventional small molecule inhibitors to target these accumulating proteins is a difficult task due to the undruggable/indestructible nature of certain protein molecules. However, the removal of these aggregates as a defense mechanism by different protein quality control systems in our body is a normal physiological process. Advancements in the field of medicinal chemistry has led to the development of various chemical mediated targeted protein degradation techniques, which target disease causing protein of interest (POI) through ubiquitin-proteasome system (UPS) to dissolve/degrade the misfolded proteins. Such methods involve the development of molecular glues, proteolysis targeting chimeras (PROTACs), autophagosome conjugated compounds, and hydrophobic tagging. This article covers a recent update on designing of PROTACs using different linkers, their mechanism of action, pharmacokinetics, in addition to advantages and disadvantages of PROTACs as therapeutic modalities to treat AD.