Research progress of proteolysis-targeting chimeras in viral hepatitis drug discovery

Proteolysis Targeting Chimera (PROTAC) is an innovative drug discovery strategy that utilizes bifunctional small molecules to bring a target protein (POI) into proximity with an E3 ubiquitin ligase, thereby inducing ubiquitination of the pathogenic protein and its subsequent degradation by the proteasome. PROTACs exhibit a novel mechanism of action, catalytic efficiency, high selectivity, and broad applicability. They have achieved significant breakthroughs, particularly in oncology, with several molecules currently in phase II/III clinical trials. The application of PROTAC technology in antiviral drug development remains in the early exploratory stage. However, since most antiviral targets are viral proteins, targeted clearance of these pathogenic proteins is unlikely to cause adverse side effects. PROTACs hold particular promise in chronic viral infections such as hepatitis B virus (HBV), where degradation of proteins like HBx and HBcAg, in combination with existing therapies, may help overcome the challenges of achieving a cure. This article summarizes recent advances in PROTAC-based anti-hepatitis research and critically discusses both the opportunities and challenges in developing PROTACs as next-generation antiviral therapeutics. It also highlights the role and characteristics of fluorine in the design of drugs for treating hepatitis.