Novel Treatment Target Against COVID-19 – Discovered!

Mechanism of therapies targeting a molecular chaperone called GRP78 might offer additional protection against COVID-19 and other coronaviruses that emerge in the future as per a study at Keck School of Medicine of USC, published in the Journal of Biological Chemistry. The spread of the deadly SARS-CoV-2 virus has been combatted by the swift development of vaccines. However, reaching herd immunity remains challenging with the rise of new mutations and the inability of immunosuppressed people to develop an effective immune response following vaccination.

Chaperones like GRP78 are molecules that aids in the regulation of the correct folding of proteins, especially when a cell is under stress. Hijacking these chaperones by viruses enable them to infect the target cells, where they reproduce and spread. GRP78 has also been implicated in the spread of other serious viruses, such as Ebola and Zika.

Role of GRP78 in COVID-19

Earlier studies provide evidence on the capacity of the SARS-CoV-2 virus to infect cells by binding with ACE2 receptors on their surface. However the present study examines the role of GRP78 as well, with the support of computer modeling predictions in COVID-19.

It was found that GRP78 serves as a co-receptor and stabilizing agent between ACE2 and SARS-CoV-2, enhancing recognition of the virus' spike protein and allowing more efficient viral entry into host cells. The more infectious COVID-19 variants are further seen to bind stronger to GRP78.

The study team treated lung epithelial cells with humanized monoclonal antibody (hMAb159) – known to remove GRP78 from the cell surface with no adverse effects in mouse models. The GRP78 was removed and ACE2 receptors on the cell surface were further reduced to diminish the number of targets to which SARS-CoV-2 could attach.

The team states that interventions, such as hMAb159, to remove cell surface GRP78 could reduce SARS-CoV-2 infection and inhibit the spread and severity of COVID-19 in infected people.

"Our study reveals that therapy targeting GRP78 could be more effective at protecting and treating people who contract COVID-19 than vaccines alone, particularly when it comes to people who can't get the vaccine and variants that could bypass vaccine protection but still depend on GRP78 for entry and production," says senior author Amy S. Lee, Ph.D., Judy and Larry Freeman Chair in basic science research and professor at the department of biochemistry & molecular medicine at the Keck School of Medicine of USC.

Hijacking of GRP78 by SARS-CoV-2 virus

The stress caused by SARS-CoV-2 infection pushes the GRP78 out to the cell surface which then facilitates binding between ACE2 and Spike protein of SARS-CoV-2. The viral hijack then allows the entry point for the virus into the cell and produces more viral proteins.

Cellular stress from other diseases like diabetes or cancer further intensifies the process, that makes people with comorbidities more susceptible to SARS-CoV-2 infection.

GRP78 as Treatment target in COVID-19

Normally, the healthy cells require a fraction of GRP78 to function at the physiological level. But, stressed cells, such as virally infected or cancerous cells, require more GRP78 to survive and multiply. Hence treatments that focus on reducing the amount of GRP78 in the body could reduce the severity of SARS-CoV-2 infection and spread without adverse effects.

The authors speculate that apart from the monoclonal antibody used in the study, other agents could also be used to reduce the amount of activity of GRP78. This creates multiple pathways for potential drug solutions to target GRP78 and is yet to be further explored through animal studies.

"What is particularly exciting for this finding is that GRP78 could be a universal target in combination with existing therapies not just to combat COVID-19, but other deadly viruses that depend on GRP78 for their infectivity as well," says Lee.



Source-Medindia