Researchers identify potential coronavirus vaccine and therapy targets

Written by Yella Hewings-Martin, Ph.D. on March 9, 2020 - Fact checked by Paula Field

 

Researchers show that antibodies that can neutralize the virus that causes SARS can reduce how well the new coronavirus infects cells in laboratory studies. They also use an approved drug to reduce virus entry into cells.

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With global cases of COVID-19 surpassing 100,000, researchers are looking for ways to prevent new viral infections.

The new coronavirus, called SARS-CoV-2, has strong similarities to other viruses in the coronavirus family, particularly those that cause SARS and MERS.

Two new papers appeared recently in the journal Cell, investigating how SARS-CoV-2 infects cells.

So, how exactly does the virus gain entry to cells, and why is it important to know this?

Understanding the target molecules that facilitate viral entry into cells is paramount to identifying how to stop this process from happening.

Both papers report that SARS-CoV-2 makes use of the same mechanism for viral entry that the SARS virus (SARS-CoV) uses.

More importantly, both research teams looked at ways of disrupting this process, using an enzyme inhibitor and antibodies against the SARS virus.

Coronavirus infection route

The new coronavirus, SARS-CoV-2, is a type of virus called an enveloped RNA virus.

This means that its genetic material is encoded in single-stranded RNA molecules surrounded by a cell membrane taken from the cell that it last infected.

When enveloped viruses infect a cell, they do this using a two-stage process.

The first step involves making a connection with a receptor on the surface of the target cell. The second is fusion with a cell membrane, either on the surface of the cell or at an internal location.

In the case of coronaviruses, the first step requires that specific proteins in the viral envelope, called spike (S) proteins, undergo a biochemical modification. This step is called S protein priming.

The enzymes responsible for S protein priming are potential therapeutic targets as inhibiting their mechanism may prevent a virus from being able to enter a cell.

“Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets,” write the authors one of the new papers in Cell.

The senior study author is Stefan Pöhlmann, a professor for Infection Biology at Georg-August-University and Head of the Infection Biology Unit of the German Primate Center, both in Göttingen in Germany.

Pöhlmann and his colleagues show evidence that the SARS-CoV-2 S protein binds to the same receptor as the SARS virus S protein. The receptor is called angiotensin-converting enzyme 2 or ACE2.

In fact, an earlier paper in the journal Nature had already implicated ACE2 as the receptor that allows SARS-CoV-2 to infect cells.

In addition to providing further evidence of ACE2’s role, Pöhlmann and the team also saw that, like SARS-CoV, the new coronavirus S protein uses an enzyme called TMPRSS2 for S protein priming.

Importantly, they showed that “camostat mesylate, an inhibitor of TMPRSS2, blocks SARS-CoV-2 infection of lung cells.”

Camostat mesylate is a drug approved in Japan for the treatment of pancreatitis. The authors explain in the paper:

“This compound or related ones with potentially increased antiviral activity could thus be considered for off-label treatment of SARS-CoV-2-infected patients.”

Towards a SARS-CoV-2 vaccine

Pöhlmann and his colleagues also studied whether antibodies made by people who had a previous diagnosis of SARS would prevent SARS-CoV-2 virus entry into cells.

They found that antibodies against the SARS-CoV S protein reduced how well a laboratory model virus with the SARS-CoV-2 S protein could infect cells. They also saw similar results with antibodies against S proteins made in rabbits.

“Although confirmation with infectious virus is pending, our results indicate that neutralizing antibody responses raised against SARS-S could offer some protection against SARS-CoV-2 infection, which may have implications for outbreak control,” the team writes in the paper.

Yet, Pöhlmann and his colleagues are not the only ones studying the potential to use antibodies to SARS as a vaccine for SARS-CoV-2.

David Veesler, an assistant professor in Biochemistry at the University of Washington in Seattle, provides more evidence that the virus enters target cells via ACE2 in a paper published in Cell.

Along with his colleagues, he also studied antibodies against SARS S protein fragments to identify potential vaccines.

The team showed that antibody serum from four different mice could reduce infection with a laboratory model virus containing the SARS-CoV-2 S by 90%.

But before a much-needed SARS-CoV-2 vaccine is available, more testing is required.

Clinical trials to show the safety and efficacy will form the basis of developing these vaccine candidates into safe products to use.

In Europe, the European Medicines Agency announced last month that it was taking “concrete actions to accelerate the development and availability of medicinal products for the treatment and prevention of the new coronavirus.”

Meanwhile, in the United States, the Department of Health and Human Services is collaborating with Janssen Research and Development, part of pharmaceutical company Johnson & Johnson, to develop a vaccine against SARS-CoV-2. A clinical trial, sponsored by the National Institute of Allergy and Infectious Diseases using a novel type of RNA-based vaccine, is also underway.