A new study suggests that a drug that showed promise in preclinical tests against treatment-resistant cancer might also work against COVID-19.
The study, led by Amy S. Lee, Ph.D., a professor of biochemistry at the Keck School of Medicine, demonstrates that GRP78, a chaperone protein previously linked to the spread of other viruses, is crucial to the transmission of SARS-CoV-2, the virus responsible for COVID-19. Furthermore, the study shows that SARS-CoV-2 replication is significantly suppressed when either GRP78 production or activity is blocked or inhibited using a novel targeted drug.
For many years, Lee has focused her research on this protein and its connection to cancer. She actually created the first human GRP78 clone. In early 2020, her lab was actively working on several projects involving GRP78’s role in cancer, including one that examined the relationship between the protein and the growth of KRAS-mutated cancer cells.
Then COVID came around, leading all labs not focused on COVID-19-related projects to shut down; Lee’s lab was no exception. But when the older writings were looked at, something interesting came up: research on other coronaviruses indicated that they used GRP78 to gain access to cells.
Seeing this, Lee prompted her team to find out whether COVID-19 might be one of those viruses, and indeed, their initial results – published last year – showed that the virus did use GRP78 to enter cells and reproduce. However, whether or not GRP78 was actually necessary for viral replication was unclear.
The team infected human lung cells with COVID-19 and monitored the levels of GRP78 to learn the answer. Scientists observed that protein levels rose as infection progressed, so they did the opposite; they prevented the protein from forming in a new set of cells and then infected the virus in them. COVID-19 spike protein and infectious virus production were reduced in GRP78-deficient cells, demonstrating the importance of this protein for viral replication.
To find out more about whether targeting GRP78 could help treat COVID-19, the researchers tried a small molecule drug called HA15 on infected lung cells to see if it worked. This drug was designed to combat cancer by binding to GRP78 and blocking its function. The drug cut down on both the size and amount of COVID-19 plaques, and the effect was stronger as the dose went up.
The team eventually moved on to using live models. They gave SARS-CoV-2-infected mice injections for three days, starting on the day they got sick. At the end of the time period, there were ten times fewer viruses in their lungs than in the controls.
Previous research by Lee with HA15 has shown that it may be effective against KRAS-mutated cancers as well. Although KRAS-mutated cancer had been considered “undruggable,” the first drug specifically targeting this subset of the disease, Amgen’s Lumakras, was only approved by the FDA last year.
In a September paper, Lee’s group reported findings that hinted that inhibiting GRP78 with HA15 could be an effective therapeutic approach. The team demonstrated that the drug, in combination with another GRP78 blocker called YUM70, was able to lower KRAS protein levels and tumors in mouse models as well as cell line models.
