A new drug shows promise in fighting both COVID-19 and cancer

messenger RNA

The “life cycle” of mRNA in a eukaryotic cell. RNA is transcribed in the nucleus; processing, it is transported to the cytoplasm and translated by the ribosome. Finally, the mRNA is degraded. Credit: Public Domain

While vaccination can provide life-saving protection against COVID-19, scientists are still looking for ways to treat severe infections, including in people who cannot get vaccinated or if dangerous new strains of the virus emerge that could bypass vaccine protection .

Now, a new study from a team of researchers led by Amy S. Lee, Ph.D., professor of biochemistry and molecular medicine at USC’s Keck School of Medicine, shows that a guidance protein known as GRP78 is involved in the proliferation. of other viruses plays an important role in the spread of SARS-CoV-2, the virus that causes COVID-19. The study also shows that blocking the production of GRP78, or blocking its activity with a new targeted drug, significantly reduced the replication of SARS-CoV-2.

The study was recently published in the journal Nature communicationsuggests that this drug could potentially offer a new type of protection against COVID-19, which could remain effective even as new strains evolve.

“A big problem in the fight against SARS-CoV-2 is that it is constantly mutating and adapting to infect and replicate more efficiently in its host cells,” said Lee, also the Judy and Larry Freeman Chair in Basic Science. “If we continue to chase the virus, it could become quite challenging and unpredictable.”

Role of GRP78 in virus propagation

Lee and her colleagues at USC’s Keck School of Medicine and the Cleveland Clinic Florida Research and Innovation Center, in search of a more sustainable method to combat COVID-19, began investigating the role of GRP78, a key cell-guided 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. Keck School of Medicine researchers showed in a 2021 paper that when SARS-CoV-2 enters the scene, GRP78 is hijacked to work in concert with other cell receptors to bring the SARS-CoV-2 virus into cells, where it can then replicate see and distribute.

But questions remain about whether GRP78 is “necessary and necessary” 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 progresses, the infected cells produce higher levels of GRP78.

The potency to inhibit 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 interfering with other cellular processes. When these cells were later infected with SARS-CoV-2, they produced less of the viral protein and released much less of the virus to infect other cells, proving that GRP78 was essential and necessary for viral replication and production.

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

To further investigate whether targeting GRP78 might work to treat COVID-19, the researchers tested a recently identified small molecule drug, known as HA15, on infected lung cells. This drug, developed for use against cancer cells, specifically binds to GRP78 and blocks 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 infected cells, at safe doses that had no adverse effects on normal cells,” Lee said. .

The researchers then tested HA15 in the bodies of mice genetically modified to express the human SARS-CoV-2 receptor and infected with SARS-CoV-2, and found that the drug significantly reduced the viral load in the lungs.

Drugs that target GRP78

Separately, Lee and her colleagues at the Keck School of Medicine are investigating the efficacy of HA15 in cancer, as well as another GRP78 inhibitor, YUM70, in collaboration with researchers at the University of Michigan. They found that HA15 and YUM70 can suppress the production of mutant KRAS proteins – a common mutation that tends to resist chemotherapy – and reduce the viability of cancer cells carrying such mutations in pancreatic, lung and colon cancers. These results were recently published in the journal A tumorsuggest that targeting GRP78 may help fight these deadly cancers.

These are basic proof of basic research; further research, including clinical trials, is needed to confirm that HA15 and YUM70 are safe and effective for human use. These and other GRP78 inhibitors are currently 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.

In addition to Lee, the Nature communication Other study authors include Dat Ha of the Department of Biochemistry and Molecular Medicine, Keck School of Medicine, USC; Keigo Machida of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC; and Woo-Jin Shin from the Florida Center for Research and Innovation, Cleveland Clinic.

More information:
Shin, WJ., Ha, DP, Machida, K. et al. The ER stress chaperone GRP78/BiP is up-regulated during SARS-CoV-2 infection and acts as a virulence protein. Nature communication, 13, 6551 (2022). doi.org/10.1038/s41467-022-34065-3

Provided by the Keck School of Medicine of USC

Quotation: New drug shows promise to fight both COVID-19 and cancer (2022, November 14) Retrieved November 14, 2022 from https://medicalxpress.com/news/2022-11-drug-covid-cancer.html

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