Pro-viral Protein Gives Hope To People Who Cannot Get Vaccinated

Even though getting vaccinated against COVID-19 can save your life, scientists are still looking for ways to treat severe infections. This is for people who can’t get vaccinated or in case dangerous new strains of the virus appear that could make the vaccine useless.

A new study conducted by Amy S. Lee, PhD, professor of biochemistry and molecular medicine at USC’s Keck School of Medicine, finds that GRP78, a chaperone protein implicated in the propagation of other viruses, plays a critical role in the spread of SARS- CoV-2, the virus that causes COVID-19. In addition, the study demonstrates that preventing the creation of GRP78 or decreasing its function with a new targeted medication significantly reduced SARS-CoV-2 replication.

The study, which was just published in the journal Nature Communications, reveals that this drug may offer a new sort of protection against COVID-19, one that may remain effective even as new strains emerge.

“A major problem in fighting SARS-CoV-2 is that it is constantly mutating and adapting itself to more efficiently infect and multiply in its host cells,” adds Lee, also the Judy and Larry Freeman Chair in basic science research. “If we keep chasing the virus around, this could become quite challenging and unpredictable.”

How GRP78 helps viruses spread

Lee and her colleagues at USC’s Keck School of Medicine and the Cleveland Clinic Florida Research and Innovation Center began investigating the role of GRP78, a key cellular chaperone protein that helps in controlling the folding of other cellular proteins, in their search for a more stable way to combat COVID-19. Cells that are healthy only need a small amount of GRP78 to work normally. Cells that are under stress, on the other hand, need more GRP78 to cope. In a publication published in 2021, Keck School of Medicine researchers demonstrated that when SARS-CoV-2 is present, GRP78 is co-opted by other cellular receptors to transport the virus inside cells, where it can replicate and proliferate.

However, it remained unclear if GRP78 is “necessary and essential” for SARS-CoV-2 replication in human lung cells. The research team looked at human lung epithelial cells infected with SARS-CoV-2 and found that when the viral infection worsens, the infected cells make more GRP78.

The ability to suppress GRP78

Then, Lee and her team suppressed the production of the GRP78 protein in human lung epithelial cells in cell culture without interfering with other cellular functions using a unique messenger RNA technique. When these cells were infected with SARS-CoV-2, they produced significantly less of the viral spike protein and released significantly less virus to infect then crucial cells, demonstrating that GRP78 was necessary and for viral replication and generation.

“We now have direct evidence that GRP78 is a proviral protein that is essential for the virus to replicate,” Lee adds.

To find out more about whether targeting GRP78 researchers could help treat COVID-19, the tried a small molecule drug called HA15 on lung cells that were infected with COVID-19. This drug, which was made to kill cancer cells, binds to GRP78 and stops it from working.

“Lo and behold, we found that this drug was very effective in reducing the number and size of SARS-CoV-2 plaques produced in the infected cells, at safe doses which had no harmful effect on normal cells,” notes Lee.

The researchers then gave HA15 to mice that had been genetically modified to express a human SARS-CoV-2 receptor and then infected with SARS-CoV-2. They found that the drug greatly reduced the amount of virus in the mice’s lungs.

Drugs targeting GRP78

Separately, in partnership with scientists at the University of Michigan, Lee and her colleagues at the Keck School of Medicine are researching the effectiveness of HA15 and another GRP78 inhibitor, YUM70, in the treatment of cancer.

They found that HA15 and YUM70 can stop the production of mutant KRAS proteins, which is a common mutation that makes it hard for drugs to work, and reduce the ability of pancreatic, lung, and colon cancer cells with these mutations to live.

These results, recently published in Neoplasia, imply that targeting GRP78 could be useful in the fight against these lethal tumors.

These are basic proof-of-concept studies. More research, including clinical trials, is needed to show that HA15 and YUM70 are safe and effective for use in humans. As potential therapies for COVID-19 and cancer, these and additional GRP78 inhibitors are currently undergoing clinical trials. According to Lee, these medicines may also prove useful in the treatment of future coronaviruses that rely on GRP78 for entry and replication.

Source: 10.1038/s41467-021-2025551-1

Image Credit: JOSEPH PREZIOSO/AFP via Getty Images

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