PROTAC (Proteolysis-Targeting Chimera) technology, by linking E3 ubiquitin ligase to the target protein, leads to the ubiquitin modification of the target protein, which is broken down into peptides and amino acids by the proteasome. After the target protein is degraded, PROTAC will be released for reuse and continue to destroy the target protein.
PROTAC has many potential advantages, such as its wide tissue distribution and oral administration. Compared with other therapies (such as cell therapy, antibody drugs, etc.), the production process of PROTAC is simpler. And compared with small molecular drugs, PROTAC can target more targets that small molecular drugs cannot, resulting in better results.
In recent years, PROTAC technology has developed rapidly and has proven to be one of the most promising and groundbreaking drug discovery technologies. Currently, PROTAC mainly targets E3 ligases such as CRBN and VHL. The discovery of new available E3 ligases and the development of corresponding PROTACs are of great importance but also face great challenges.
Researchers Cen Shan, Liyan Yu, and Fei Guo, as co-corresponding authors, published a research paper entitled: An anti-influenza A virus microbial metabolite acts by degrading viral endonuclease PA in Nature Communications online.
This study found that the microbial natural product APL-16-5, which combines E3 ubiquitin ligase TRIM25 and influenza virus PA subunit, induces TRIM25-dependent PA ubiquitination and its degradation based on PROTAC mechanism, blocks virus RNA replication, and has good anti-influenza A virus activity in vivo.
This study also identified the first PROTAC molecule derived from a natural product of microorganisms, suggesting that microbial metabolites could be an important source for the discovery of natural PROTAC molecules.
As the first PROTAC molecule with high antiviral activity in vivo, APL-16-5 has the potential to develop into a new type of anti-influenza drug to solve the problem of antigen drift and drug resistance to the influenza virus. In particular, this study proposed and verified for the first time that TRIM25 can be used as a new E3 ubiquitin ligase for PROTAC technology. In view of the fact that the trim superfamily is one of the largest E3 ubiquitin ligase families (nearly 80 members) in vivo, its application in drug research and development may greatly expand the development potential of PROTAC technology. At the same time, APL-16-5 and its derivatives can be used as TRIM25 ligands to promote new TRIM25-based PTOTAC molecular design and further expand its scope of application.