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Researchers at the University of Southern California and the Cleveland Clinic Florida Research and Innovation Center have published new research on GRP78, a protein involved in both diseases, novel coronavirus pneumonia, as well as multiple forms of cancer, as well as a new drug
that can interfere with its effects.
Despite the potentially life-saving protection that vaccination can provide against COVID-19, researchers are still looking for effective ways to treat serious infections, including treating those who cannot be vaccinated or in the event of the emergence of dangerous new strains of the
virus that could bypass vaccine protection.
A new study led by Amy S.
Lee, Ph.
D.
, professor of biochemistry and molecular medicine at the Keck School of Medicine at the University of Southern California, has found that GRP78, a chaperone protein involved in the spread of other viruses, plays a key role
in the spread of the SARS-CoV-2 virus that causes COVID-19.
The study also showed that SARS-CoV-2 replication was significantly reduced
by blocking GRP78 production or inhibiting GRP78 production with new targeted drugs.
According to the study, recently published in the journal Nature Communications, the drug may provide a new type of protection against COVID-19 that may still be effective
even if a new strain emerges.
"A major problem in the fight against SARS-CoV-2 is that it constantly mutates and adapts to infect host cells more efficiently and multiply
in its cells," Lee said.
If we continue to chase the virus, this can become quite challenging and unpredictable
.
”
In search of a more stable way to fight COVID-19, Lee and her colleagues at the Keck School of Medicine at USC and the Cleveland Clinic Florida Research and Innovation Center set out to study the role of GRP78, a key cell chaperone protein that helps regulate the folding
of other cellular proteins.
Healthy cells need a small fraction of GRP78 to function properly, while cells under stress need more GRP78 to cope
.
Researchers at Keck School of Medicine demonstrated in a 2021 study that when SARS-CoV-2 enters the field, GRP78 is hijacked and works with other cellular receptors to bring the SARS-CoV-2 virus into cells, where it then multiplies and spreads
.
But GRP78 remains questionable
about whether SARS-CoV-2 replication is "necessary and necessary" in human lung cells.
The team examined human lung epithelial cells infected with SARS-CoV-2 and found that as the virus infection intensified, the levels of GRP78 produced by the infected cells increased
.
Lee and her team then used a special messenger RNA tool to inhibit the production of the GRP78 protein in human lung epithelial cells in cell culture without interrupting other cellular processes
.
When these cells were later infected by SARS-CoV-2, they produced a lower amount of viral spike protein and released a much smaller number of other cells that infected the virus, demonstrating that GRP78 is necessary
for viral replication and production.
"We now have direct evidence that GRP78 is a proviral protein
necessary for viral replication," Lee said.
To further explore whether targeting GRP78 could treat COVID-19, the researchers tested a recently discovered small molecule drug, HA15
, on infected lung cells.
Developed to fight cancer cells, the drug specifically binds to GRP78 and inhibits its activity
.
"You see, we found that this drug was very effective at reducing the number and size of SARS-CoV-2 plaques produced in infected cells at safe doses, with no harmful effects on normal cells," Lee said
.
The researchers then tested HA15 in mice genetically engineered to express human SARS-CoV-2 receptors and were infected with SARS-CoV-2 and found that the drug greatly reduced the viral load in the lungs
.
Separately, Lee and her colleagues at Keck School of Medicine are working with researchers at the University of Michigan to study the efficacy of HA15 in cancer, as well as another GRP78 inhibitor, YUM70
.
They found that HA15 and YUM70 inhibited the production of mutant KRAS protein—a common mutation that tends to resist drug treatment—and reduced the viability
of cancer cells carrying this mutation in pancreatic, lung, and colon cancers.
The findings, recently published in the journal Neoplasia, suggest that targeting GRP78 may help fight these deadly cancers
.
These are the basic proofs of principle research; Further research, including clinical trials, is needed to determine whether HA15 and YUM70 are safe and effective
for human use.
These and other GRP78 inhibitors are currently being tested
as treatments for COVID-19 and cancer.
The drugs could also prove useful
in treating future coronaviruses that rely on GRP78 entry and replication, Lee said.
The study, which was promoted by the USC Biosafety Level 3 Containment Laboratory, allowed the team to safely study SARS-CoV-2 infection
in genetically modified mice.
References:
1.
“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.
2.
“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.
