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The decoy receptor inactivates Coronavirus SARS-CoV-2 / COVID-19 in cell culture



Coronavirus COVID-19 animation

As COVID-19 As the pandemic continues to spread, scientists and healthcare providers are looking for ways to keep coronaviruses from infecting tissues when they come into contact. A new study shows that luring the virus with bait – a designed free-floating receptor protein ̵

1; binds to the virus and stops infection.

Erik Procko, professor of biochemistry at the University of Illinois, Urbana-Champaign, leads the study, is published in the journal Science.

To infect human cells, the virus must first bind to a receptor protein on the cell surface. SARS-CoV-2The coronavirus that causes COVID-19, which binds to a receptor called ACE2, has a number of roles in regulating blood pressure, blood volume, and inflammation. It is found in tissues throughout the body, but especially in the lungs, heart, arteries, kidneys, and intestines. Many researchers hypothesize that the host of COVID-19-related symptoms may originate from the coronavirus that binds to ACE2 and makes it inactive.

“Using an ACE2-based decoy can not only neutralize the infection, but also have the added benefit of salvaging lost ACE2 activity and directly treating aspects of COVID,” Procko said. 19.

As a potential therapeutic agent, the decoy receptor has an advantage over other drugs: To avoid it, the virus will have to mutate in a way that makes it less infectious.

“The benefit of a decoy receptor is that it closely resembles a natural receptor. Therefore, the virus cannot easily adapt to escape the neutralization without simultaneously losing its ability to bind to its natural receptors. This means that the virus has limited resistance, ”said Procko.

Although ACE2 binds to SARS-CoV-2, it is not optimized for that purpose, meaning that subtle mutations to the receptor could cause it to bind more strongly. This makes it an ideal candidate for a decoy receptor, Procko said.

Procko tested more than 2,000 ACE2 mutations and created cells with mutant receptors on their surfaces. By analyzing how these interact with the coronavirus, he found the combination of three mutations that form a virus binding receptor 50 times stronger, making it a much more attractive target for the virus. virus.

Procko then creates a soluble version of the designed receptor. Separated from the cell, the soluble receptor is suspended in solution and freely interacts with the virus as a decoy receptor.

After Procko posted his findings to a pre-printed server, a colleague connected him to the US Army’s Institute of Infectious Diseases. Researchers there, along with the laboratory of biochemistry professor David Kranz in Illinois, verified a strong affinity between the virus and the decoy receptor, comparable to the best antibodies identified up to now, says Procko. Furthermore, they found that the decoy receptor not only binds to the virus in living tissues, but it effectively deactivates it, preventing the cells from becoming infected.

More work is needed to determine if the decoy receptors can be an effective treatment or a preventive agent against COVID-19.

“We are testing whether the bait’s receptors are safe and stable in mice, and if successful, we hope to treat the disease in animals. Hopefully that data can facilitate a clinical trial, ”said Procko. He is also exploring how decoy receptors that bind to other coronaviruses have the potential to become pandemic in the future if they are passed from bats to humans.

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Reference: “Human ACE2 technique to optimize binding to mutant 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, August 4, 2020, Science.
DOI: 10.1126 / science.abc0870

The National Institutes of Health supported this work.




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