Cornell Researchers Target Coronavirus Membrane Fusion Mechanism for Antiviral Development

A team of researchers from Cornell University (Ithaca, NY, USA) has proposed that blocking membrane fusion – a critical part of the mechanism by which coronaviruses spread – could offer a potential target for antiviral treatment for COVID-19.

The researchers initially set out to analyze the structure and characteristics of SARS-CoV (severe acute respiratory syndrome coronavirus) and MERS-CoV (Middle East respiratory syndrome coronavirus), with a focus on the spike protein – specifically the fusion peptide – that allows these viruses to infect cells by transferring their genome. As the current pandemic escalated, the researchers compared the biological sequences of the fusion peptides of SARS-CoV to SARS-CoV-2, the virus that causes COVID-19, and found them to be a 93% match.

According to the researchers, blocking the fusion step is significant as the fusion machinery does not evolve and change as fast as other parts of the protein does. It has been built specifically to merge the two membranes together and developing antiviral strategies to reduce that efficiency could potentially result in very broadly-acting treatments. The team of researchers is now drilling down into the intricate procedure of membrane fusion, or the mechanism by which coronaviruses spread.

Membrane fusion is a multistep process that begins with the virus recognizing that it’s found the right type of cell to infect. To do this, the virus receives feedback from the chemical environment, including cues like the receptor that the host cell presents. The virus then attaches to the host cell receptor by way of the spike protein. Next, a piece of the spike protein, called the fusion peptide, interacts directly with the host cell membrane and facilitates merging to form a fusion pore, or opening. The virus then transfers its genome into the host cell through this pore. These genomic instructions essentially commandeer the host’s machinery to produce more viruses. These interactions can be difficult to parse through traditional approaches because the fusion process is dynamic and flexible, and the spike protein changes its shape drastically during fusion.

The researchers then used a variety of spectroscopic methods, including electron spin resonance and nuclear magnetic resonance, respectively, to more closely analyze the fusion peptide’s structure and function. They found that calcium ions interacting with the fusion peptide can change the peptide’s structure, and how it interacts with membranes in ways that promote infection in MERS and SARS. The researchers are now turning their attention to SARS-CoV-2 as the fusion peptides are consistent in all three viruses. The team is hopeful the research can illuminate some of the chemistry-related questions surrounding COVID-19, such as how it was able to move into humans, what chemical cues facilitated that process, and why the virus is able to replicate so easily in the respiratory tract.

“The subtleties are what make this virus so interesting. For some viruses, calcium has no effect on infection, but for coronavirus, we are seeing that it does,” said Susan Daniel, associate professor of chemical and biomolecular engineering, who led the multidisciplinary group. “And this points us to thinking about how this might be a target for developing antiviral drugs or repurposing already approved calcium-blocking drugs. Based on what we know, we believe that targeting the fusion machinery for drug development is an astute choice.”

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