COVID’s – and other viruses’ – Achilles' heel identified
Researchers have identified how the SARS-CoV-2 virus that causes COVID-19 takes advantage of our cellular machinery to replicate and spread in the body, and, importantly, a way to stop it. The finding could lead to the development of a new class of antiviral therapies to treat not only SARS-CoV-2, but other viruses as well.
Genetic instructions in our cells are transcribed from DNA to messenger RNA (mRNA), then translated into proteins that enable functions such as cell-to-cell communication. After translation, these proteins often need additional modifications, called post-translational modifications, to ensure they perform effectively. SUMOylation is one such post-translational modification that directly regulates viral replication and the body’s innate immune response.
Researchers from the University of California Riverside examined the post-translational modification mechanism that occurs during infection with SARS-CoV-2 to see if there is a way to stop its spread.
A core component of the SARS-CoV-2 virus is the nucleocapsid (N) protein, mainly responsible for packaging RNA in a protective covering. SUMOylation directs the virus’ N protein to the right location for packaging after it infects human cells. Once it’s in the right place, the protein begins inserting copies of its genes into new infectious virus particles, virions, which spread and make us sicker.
“In the wrong location, the virus cannot infect us,” said Quanqing Zhang, one of the study’s co-authors. “If someone gets an infection, maybe one of his or her proteins will appear differently than it was before. That’s what we’re looking for.”
The researchers used fluorescence to make the SARS-CoV-2 virus’ post-translational modifications easier to see.
“We used fluorescent glow to show us where the virus is interacting with human proteins and making new virions – infectious viral particles,” said Jiayu Liao, corresponding author of the study. “This method is more sensitive than other techniques and gives us a more comprehensive view of all the interactions between the human and viral proteins.”
The researchers used the same method in a previous study, finding that the two most common types of flu virus, Influenza A and B, require the same post-translational SUMOylation modification to replicate.
In the current study, they identified three SUMOylation sites on the SARS-CoV-2 N protein. One of the sites, K65, was critical to the protein’s nuclear translocation, or the movement of proteins into the cell’s nucleus, a novel feature of the SARS-CoV-2 virus. The researchers concluded that the spread of the virus depends on SUMOylation proteins and that blocking access to the proteins would enable our immune system to kill it.
Currently, the most effective treatment for COVID-19 is Paxlovid, which inhibits viral replication. But it needs to be commenced within three days of infection for it to be most effective.
“If you take it after that, it won’t be so effective,” said Liao. “A new medication based on this discovery would be useful to patients in all stages of infection.”
The researchers say identifying the similarity of action between SARS-Cov-2 and the influenza virus may lead to the development of a new class of antiviral medications with broad application.
“I think other viruses might work this way as well,” Liao said. “Ultimately, we would like to block the flu as well as COVID, and potentially other viruses such as RSV [respiratory syncytial virus] and Ebola. We are making new discoveries to make this happen.”
The study was published in the journal Viruses.
Source: UC Riverside