Antiviral PROTACs: Opportunity borne with challenge

Proteolysis targeting chimera (PROTAC) degradation of pathogenic proteins by hijacking of the ubiquitin-proteasome-system has become a promising strategy in drug design. The overwhelming advantages of PROTAC technology have ensured a rapid and wide usage, and multiple PROTACs have entered clinical trials. Several antiviral PROTACs have been developed with promising bioactivities against various pathogenic viruses. However, the number of reported antiviral PROTACs is far less than that of other diseases, e.g., cancers, immune disorders, and neurodegenerative diseases, possibly because of the common deficiencies of PROTAC technology (e.g., limited available ligands and poor membrane permeability) plus the complex mechanism involved and the high tendency of viral mutation during transmission and replication, which may challenge the successful development of effective antiviral PROTACs. This review highlights the important advances in this rapidly growing field and critical limitations encountered in developing antiviral PROTACs by analyzing the current status and representative examples of antiviral PROTACs and other PROTAC-like antiviral agents. We also summarize and analyze the general principles and strategies for antiviral PROTAC design and optimization with the intent of indicating the potential strategic directions for future progress.