Grant: Project Grant

Effective strategies to treat viral disease rely on our ability to interfere with viral infection and/or replication. In recent years, abnormalities in protein turnover states have been frequently observed in various human diseases caused by viral pathogens. This can be attributed to the misbehaviour of a cellular machinery that employs a small protein called ubiquitin, which attaches to target proteins and acts as a signal for their destruction. Therefore, pathogenic effectors that mimic human deubiquitinases (enzymes that remove ubiquitin from proteins) have attracted increasing attention as novel targets for drug development. Unfortunately, the lack of selective molecules to block the function of these enzymes has severely hampered attempts to manipulate them for therapeutic benefits. The goal of this project is to develop highly specific and potent inhibitors for viral deubiquitinases. Using protein engineering technology, we propose to make ubiquitin mimics that will associate tightly with these enzymes in a manner that inhibits function. We will validate their inhibitory function in mammalian cells using established biological assays. Additional structural analyses of critical contacts that mediate specificity and affinity will further aid the development of chemical inhibitors as drugs. In conclusion, this work will generate invaluable tools to understand and modulate activity of pathogenic deubiquitinases and will open new routes to effective antiviral therapy.