As de COVID-19 pandemic continues to spread, scientists and healthcare providers are looking for ways to keep the coronavirus from becoming infected once they are exposed. A new study suggests attracting the virus with a decoy – an engineered, free-floating receptor protein – binds the virus and blocks infection.
Erik Procko, a professor of biochemistry at the University of Illinois, Urbana-Champaign, led the study, published in the journal Science.
To infect a human cell, a virus must first bind to a receptor protein on the cell surface. SARS-CoV-2, the coronavirus that causes COVID-19, binds to a receptor called ACE2, which plays a number of roles in regulating blood pressure, blood pressure, and inflammation. It is found in tissue throughout the body, but especially in the lungs, heart, arteries, kidneys, and intestines. Many researchers hypothesize that the host of symptoms associated with COVID-19 may stem from the binding of the coronavirus to ACE2 and the prevention of doing its job.
“Controlling an ACE2-based happiness agent can not only neutralize infection, but can have the added benefit of losing ACE2 activity and direct treatment of aspects of COVID-19,” Procko said.
As a potential therapeutic agent, a decoy receptor has one advantage over other drugs: To evade it, the virus would have to mutate in a way that would make it less infectious.
“One advantage of a decoy receptor is that it closely resembles the natural receptor. Therefore, the virus cannot easily adapt to neutralization of escape without at the same time losing its ability to bind to its natural receptor. This means that the virus has limited ability to resist, “said Procko.
Although ACE2 binds to SARS-CoV-2, it is not optimized for that purpose, which means that subtle mutations to the receptor may bind it more strongly. This makes it an ideal candidate for a decoy receptor, Procko said.
Procko investigated more than 2,000 ACE2 mutations and made cells with the mutant receptors on their surfaces. By analyzing how these interacted with the coronavirus, he found a combination of three mutations that produced a receptor that bound to the virus 50 times stronger, making it a much more attractive target for the virus.
Procko then made a soluble version of the engineered receptor. Detached from cells, the soluble receptor is suspended in solution and free to interact with the virus as a decoy receptor.
After posting Procko’s findings on a preprint server, a colleague contacted him at the U.S. Army Medical Research Institute of Infectious Diseases. Researchers there, along with the lab of Illinois biochemistry professor David Kranz, verified the strong affinity between the virus and the decoy receptor, and competed with the best antibodies identified to date, Procko said. Furthermore, they found that the decoy receptor not only binds to the virus in living tissue cultures, it neutralizes it effectively, and prevents cells from becoming infected.
Further work is needed to determine whether the decoy receptors can be an effective treatment of as a preventive measure against COVID-19.
“We are testing whether the decoy receptor is safe and stable in mice, and if they are successful, we hope to see treatment of disease in animals. Hopefully, that data can facilitate a clinical trial, “Procko said. He also investigates how the decoy receptor binds to other coronaviruses with the potential to become future pandemics as they spread from bats to humans.
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Reference: “Engineering human ACE2 to optimize the binding to the spike protein of SARS coronavirus 2” by Kui K. Chan, Danielle Dorosky, Preeti Sharma, Shawn A. Abbasi, John M. Dye, David M. Kranz, Andrew S Herbert and Erik Procko, 4 August 2020, Science.
DOI: 10.1126 / science.abc0870
The National Institutes of Health supported this work.
