University of Southern California and the Cleveland Clinic Florida Research and Innovation Center researchers have published new research on GRP78, a protein implicated in both COVID-19 and numerous forms of cancer, as well as a new drug that interferes with its effects.
While vaccination can provide potentially life-saving protection against COVID-19, researchers are still looking for effective ways to treat severe infections, including in those who cannot get the vaccine or in the event that dangerous new virus strains emerge that could bypass vaccine protection.
A new study led by Amy S. Lee, Ph.D., professor of biochemistry and molecular medicine at the University of Southern California’s Keck School of Medicine, finds that GRP78, a chaperone protein involved in the spread of other viruses, plays a critical role in the spread of SARS-CoV-2, the virus that causes COVID-19. The research also demonstrates that SARS-CoV-2 replication was significantly decreased by preventing GRP78 production or by inhibiting it through the use of a new targeted drug.
According to the study, which was recently published in the journal Nature Communications, this drug may potentially offer a new type of protection against COVID-19, one that might remain effective even as new strains develop.
“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,” said 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.”
GRP78’s role in the spread of viruses
In search of a more stable way to combat COVID-19, 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 regulate the folding of other cellular proteins. While healthy cells need a fraction of GRP78 to function normally, cells under stress need more GRP78 to cope. The Keck School of Medicine researchers demonstrated in a 2021 study that when SARS-CoV-2 enters the scene, GRP78 is hijacked to operate in tandem with other cellular receptors to bring the SARS-CoV-2 virus into cells, where it can then multiply and spread.
But questions remained about whether GRP78 is “necessary and essential” for SARS-CoV-2 replication inside human lung cells. Examining human lung epithelial cells infected with SARS-CoV-2, the research team observed that as the viral infection intensifies, the infected cells produce higher levels of GRP78.
The power of inhibiting GRP78
Then Lee and her team used a special messenger RNA tool to suppress the production of the GRP78 protein in human lung epithelial cells in cell culture, without interrupting other cellular processes. When those cells were later infected with SARS-CoV-2, they produced a lower amount of the viral spike protein and released much less of the virus to infect other cells, proving that GRP78 was necessary and essential for viral replication and production.
“We now have direct evidence that GRP78 is a proviral protein that is essential for the virus to replicate,” Lee said.
To further explore whether targeting GRP78 could work to treat COVID-19, the researchers tested a recently identified small molecule drug, known as HA15 on the infected lung cells. This drug, developed for use against cancer cells, specifically binds GRP78 and inhibits its activity.
“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, in safe doses which had no harmful effect on normal cells,” Lee said.
The researchers then tested HA15 in the body of mice that were genetically engineered to express a human SARS-CoV-2 receptor and infected with SARS-CoV-2, finding that the drug greatly reduced viral load in the lungs.
Drugs that target GRP78
Separately, Lee and her colleagues at the Keck School of Medicine are studying the efficacy of HA15 in cancer, as well as another GRP78 inhibitor, YUM70, in collaboration with researchers at the University of Michigan. They discovered that HA15 and YUM70 can suppress the production of mutant KRAS proteins—a common mutation that tends to resist drug treatment—and reduce the viability of cancer cells bearing such mutations in pancreatic, lung, and colon cancer. Those findings, recently published in the journal Neoplasia, suggest targeting GRP78 may help combat these deadly cancers.
These are basic proof of principle studies; further research, including clinical trials, is needed to establish that HA15 and YUM70 are safe and effective for use in humans. These and other GRP78 inhibitors are now being tested as treatments for both COVID-19 and cancer. These drugs may also prove useful for treating future coronaviruses that depend on GRP78 for entry and replication, Lee said.
References: “The stress-inducible ER chaperone GRP78/BiP is upregulated during SARS-CoV-2 infection and acts as a pro-viral protein” by Woo-Jin Shin, Dat P. Ha, Keigo Machida and Amy S. Lee, 14 November 2022, Nature Communications.
“Targeting GRP78 suppresses oncogenic KRAS protein expression and reduces viability of cancer cells bearing various KRAS mutations” by Dat P. Ha, Bo Huang, Han Wang, Daisy Flores Rangel, Richard Van Krieken, Ze Liu, Soma Samanta, Nouri Neamati and Amy S. Lee, 24 September 2022, Neoplasia.
The research was funded by the National Institutes of Health, the W. M. Keck Foundation, and the Korea Research Institute of Bioscience and Biotechnology.
This research is facilitated by USC’s Biosafety-Level 3 containment laboratory, allowing the team to safely study the SARS-CoV-2 infection in genetically engineered mice.