Influenza viruses are becoming more resistant to drugs. For this reason, humans need new active ingredients. In a new study, researchers from the University of Munster in Germany provided important findings that in order to proliferate the virus, the polymerase of influenza A virus (IAV) must be ubiquitinated through enzymes in host cells. They were able to construct a comprehensive map of the ubiquitination modification. Drugs targeting these enzymes will be robust to the rapid variation of this virus, thus providing great potential for the future. The results were published in the Nature Communications journal on February 11,2023, with the title "The ubiquitination landscape of the influenza A virus polymerase".
Every year the flu season challenges hospitals. Despite being vaccinated, older adults and patients with health problems are at greater risk of severe influenza attacks. The insidious of influenza viruses is their ability to change rapidly, which makes them increasingly resistant to drugs. Therefore, there is an urgent need for new active ingredients to be able to continue providing effective treatment for this disease in the future.
In the new study, these authors took an important step in this direction, providing evidence for 59 specific modifications of the polymerase (in other words, the decisive enzyme responsible for the production of the viral genome). The feature of the modifications described in that study is that they are implemented by proteins in the host cell and that they cannot mutate rapidly compared to viral proteins. Therefore, they represent a promising approach to developing new drugs.
Influenza A virus polymerase (IAV polymerase) is a highly complex protein that has more than one function. One of them is that after the structure is changed, it can also make copies of the viral genome (cRNA and vRNA). Without this "switch" of function, the virus cannot proliferate.
As the corresponding author of the paper, Dr Linda Brunotte, and the first author of the paper, Dr Franziska Gunl and colleagues now find, IAV polymerase requires proteins from the host cell to act as a "molecular switch" and perform its different functions. These host proteins dock the so-called ubiquitin proteins at specific positions of the IAV polymerase and thus trigger a signal for this functional switch.
Dr. Brunotte explained, " We were able to construct a map showing the 59 sites on the IAV polymerase to which ubiquitin is attached via host cell proteins. These entirely new discoveries reveal the Achilles' heel of the influenza A virus.”
At 17 sites, this ubiquitination has a clear effect on the IAV polymerase activity. Furthermore, these authors identified a specific site to which ubiquitination modification represents a signal for relevant functional switching in IAV polymerase. So Dr Gunl is now looking into the future: " Based on the ubiquitination map we constructed, we can now further investigate which enzymes are specifically responsible for the modification of IAV polymerases. Drugs targeting these enzymes will be resistant to mutations in influenza viruses, thus showing great potential for future therapies."
