Proteolysis-targeting chimeras (PROTACs) are attracting more attention today as a potential treatment for cancer and other diseases. PROTACs consist of ligands, E3 ligase recruitment elements, and junctions of target proteins. PROTACs can hijack the intrinsic intracellular ubiquitin-proteasome system to degrade different target proteins.
Although small molecule modulators targeting tumor cells are widely used, they still have some drawbacks such as drug resistance, toxicity, and poor selectivity. PROTAC holds promise as a new therapeutic strategy to overcome the drawbacks of these drugs.
Neurodegenerative diseases are caused by the loss of neurons or their myelin sheaths. β-amyloid (Aβ) cascade and pathogenic tau protein are more like to be the target. Several cases of peptide-based PROTAC and small molecule-based PROTAC have been reported to degrade tau proteins, with important implications for the treatment of neurodegenerative diseases.
Autoimmune diseases are those in which the body's immune response to self-antigens leads to damage of its own tissues and even to organ failure and death. For example, IRAK4, a key signal transducer, and kinase downstream of the Toll signaling pathway is involved in mediating various inflammatory responses. PROTAC molecules have been developed to target IRAK4 for degradation to achieve anti-inflammatory and immune-modulating functions.
Hepatitis B virus (HBV) is the leading cause of acute and chronic hepatitis B. X-protein, a transactivator in HBV, plays an important role in the pathogenesis of HBV-induced hepatocellular carcinoma (HCC). Several peptide-based PROTAC molecules targeting X-proteins have been reported, which deserve to be investigated in preclinical studies for their ability to treat HBV infection and/or HCC.
