The coronavirus that causes COVID-19 infects cells by inserting into its surface receptor. Now, by creating a “bait” for its receptor, scientists are aiming to stop virus attacks.
New research published in journal August 4 Science, Researchers have designed such decoys, Coronavirus The virus was unable to infect primate cells in the dish when bound and attached tightly to the false receptor. Decoys bind to the virus as strongly as neutralize antibodyY-shaped molecule generated by Immune system Grab the virus and prevent it from infecting cells.
Neutralizing antibodies are “the best thing the human body can produce… that’s our goal.” — Research chemist at the University of Illinois at Urbana has a decoy receptor that attaches tightly to the coronavirus. Associate Professor Erik Procko-Champaign told Live Science. The team found that the newly designed decoy (known as sACE2.v2.4) received both a novel coronavirus and SARS-CoV, a related virus that caused the outbreak of severe acute respiratory syndrome in the early 2000s. It has been found to bind strongly to.
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If the decoy functions in animals in the same way that cell cultures do, it could develop into COVID-19 treatments and preventive treatments in humans. However, the study is still in its infancy and the decoy receptor has never been approved for the treatment of infections, Procco said.
“If this succeeds, this will be something new,” he said, making it the first decoy approved as an antiviral drug.
Decoy design
Several decoy receptors have been approved by the US Food and Drug Administration (FDA) for the treatment of rare inflammatory and immune system-related disorders “Familiar cold autoinflammatory syndrome” According to a 2013 report in the journal, it causes recurrent fever, joint pain, and eye irritation Immunology frontier.. However, the decoy receptor, developed as an antiviral treatment, has historically been an obstacle to approval.
The first decoy designed to block the virus mimics a natural receptor on immune cells called CD4, HIVAccording to a 2008 report in the journal Current Opinion on Biotechnology.. Although promising in studies using laboratory-grown HIV strains, the report showed that CD4 decoy did not bind effectively to strains isolated from HIV / AIDS patients. To date, no CD4 decoy has completed clinical trials and is approved for use in patients. The same is true for decoys designed to treat rhinoviruses, Foot-and-mouth disease virus, Hepatitis A and SARS-CoV.
Procco noted that decoy receptors must meet two major criteria for successful antiviral drugs.
First, natural receptors often play multiple roles in the body, so they should not interfere with important body functions. For example, the ACE2 receptor that COVID-19 uses as a gateway to cells also helps control blood volume and lower blood pressure, he said. By infecting cells with the ACE2 receptor, COVID-19 actually interferes with ACE2 activity in the body — the decoy ACE2 receptor opens its native receptor for commercial use rather than binding to coronavirus Leaving it can potentially “save” some of the lost activity, Proko said.
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But decoy ACE2 receptors can cause unexpected side effects, so researchers added that they should be monitored in animal studies and early clinical trials.
In addition to being safe to administer, the decoy receptor must have a high affinity for the target virus. That is, the decoy receptor binds strongly to the virus in human cells.
“To be a good binder and have a good affinity, you need to bind to the target quickly, and then slowly slip off the target,” Procco said. To find a decoy that binds well to SARS-CoV-2, Procko and his colleagues ruled out thousands of inappropriate ACE2 copycats using an technique called “deep mutagenesis.” ..
So what is deep mutagenesis? Think of a Vegas slot machine. Three different fruit combinations are equal or not equal to a particular payout. So is DNA. A set of three-letter codes that represent a single amino acid or protein building block. In this case, the team has scrambled 117 three-letter segments of human DNA, where previous studies have suggested that coronavirus binds strongly to the ACE2 receptor. This allowed researchers to basically “pull the levers of the slot machine” to exchange each amino acid (one spin of the slot machine) for another amino acid, thus demonstrating how ACE2 receptors bind to coronaviruses. Could be investigated. In this case, the scrambled DNA was expressed in different versions of human cells in dishes.
“We can thoroughly test thousands or thousands of mutations to see which are related,” Proko said.
After producing cells with a mutated ACE2 receptor (based on a scrambled DNA segment), the researchers found that a portion of SARS-CoV-2, known as the receptor binding domain, was locked to the ACE2 receptor. I exposed the cells. They found that sACE2.v2.4 showed the highest affinity for the virus. Later, researchers developed a version of decoy that could exist in the body without being attached to cells. Separated receptors are necessary for future drugs.
Next steps
Compared to the unmodified ACE2 receptor, “less than 1% of the total protein sequence has been altered to make a decoy,” Proko said. When fully developed as a human therapeutic, decoy receptors are likely to be delivered into the body through injection or inhaled as a mist, he said. He said that bio-based drugs such as decoy receptors are “frequently long-lived” and can persist in the body for over a week.
The decoy receptor is Antibody cocktail Designed to treat COVID-19, it contains multiple antibodies that bind to SARS-CoV-2 in different ways. However, the report published in the journal on June 15 Science Procco suggests that the virus can mutate to escape the grasp of specific antibodies. Decoy receptors can be reliable in the long run. The fact that sACE2.v2.4 binds strongly to both SARS-CoV-2 and its predecessor, SARS-CoV, makes this concept an idea given that both viruses use ACE2 to enter cells. Support
Earlier this year, Procko founded a start-up company called Orthogonal Biologics to continue his research on ACE2 decoys, and also acted as research author CEO Kui Chan. The next step is to do animal testing and they have to show that the decoy can be reliably manufactured on a large scale if the treatment goes to human studies.
Interestingly, the anACE2 decoy, developed by researchers associated with Apeiron Biologics, has already been tested in clinical trials for the treatment of COVID-19, so far in healthy people and with lung disease. Seems safe for both people. According to the statement From the company. The main difference is that the existing decoys mimic the natural ACE2 receptor and have not been mutated to bind SARS-CoV-2 as tightly as possible, whereas sACE2.v2.4 does. (Proko and his colleagues were not involved in the design of Apeyron’s decoy.)
Apeiron developed an existing decoy following the SARS epidemic as a treatment for coronavirus, but also tested drugs for various lung diseases such as acute respiratory distress syndrome (ARDS) and pulmonary arterial hypertension. Based on initial data, patients appear to be well tolerated without major side effects. Apelon products are different from those developed by the decoy Proco and his colleagues, but the initial results are promising, Proco said. “We know you can inject [the Apeiron decoy] It does not hurt or harm people.”
“The toxicity has not been observed yet,” Procko’s team began testing decoys in mice infected with COVID-19, he said.
Originally published in Live Science.
