The coronavirus that causes COVID-19 to infect cells by plugging into a receptor on their surface. Now, by fabricating a “decoy” of that receptor, scientists aim to stop the virus from attacking.
In a new study, published August 4 in the journal Science, researchers have designed such a decoy and found that Coronavirus binds tightly to the spoof receptor, and once attached, the virus is unable to infect the primate cells in a lab dish. The lure binds closely with the virus as a neutralizer antibody, a Y-shaped molecule is produced by immune system to take the virus and prevent it from infecting cells.
Study author Erik Procko, assistant professor of biochemistry at the University of Illinois at Urbana, study author Erik Procko, study author Erik Procko, associate professor of biochemistry at the University of Illinois at Urbana- Champaign, told Live Science. The team found that their newly designed decoy, called sACE2.v2.4, binds closely to both the new coronavirus and SARS-CoV, a virus linked to outbreaks of respiratory syndrome. Severe acute absorption in the early 2000s.
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If the decoy works in the animal as it does in cell culture, it could be developed into therapeutic and preventive therapy for COVID-19 in humans. That said, the study is still in a very early stage and there are no approved decoy receptors to treat an infectious disease, Procko said.
“This will be something new, if it succeeds,” he said, because it will be the first decoy to be approved as an antiviral.
Several decoy receptors have been approved by the US Food and Drug Administration (FDA) to treat diseases related to the immune system and inflammation, such as rare diseases. “Family cold self-inflammatory syndrome” causing recurrent fever, joint pain and eye inflammation, according to a 2013 report in the journal Borders in Immunology. However, the lure receptors developed as antiviral treatments once encountered road-approved obstacles.
The first lure is designed to stop a virus from mimicking a receptor naturally found on immune cells called CD4, which binds to HIV, according to a 2008 report in the journal Current opinion in biotechnology. Although promising in studies using HIV strains grown in laboratories, CD4 decoys are not effectively linked with strains isolated from HIV / AIDS patients, according to the report. To this day, no CD4 lure is clinically tested and approved for use in patients. This is also true of decoys designed to treat rúthinovirus, foot-and-mouth virus, hepatitis A and SARS-CoV.
Procko notes that, in order to be a successful antiviral, a decoy receptor must meet two main criteria:
First, it must not disrupt important bodily functions, as natural receptors often play many roles in the body. For example, the ACE2 receptor, which COVID-19 exploits as an entrance to cells, also helps control blood flow and lower blood pressure, he said. By infecting cells with ACE2 receptors, COVID-19 actually interferes with the ACE2 activity in the body – a decoy ACE2 receptor has the ability to “rescue” some of these lost activities by ways for natural receptors to act, rather than bind to coronavirus, says Procko.
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However, the lure ACE2 receptors can cause unforeseen side effects, so researchers need to follow them up in animal studies and initial clinical trials, he said. more.
In addition to safe management, the decoy receptor must exhibit a high affinity for the virus it targets, meaning it binds closely to the virus in human cells.
“To be a good, high-bonded binder, you need to align with your goals quickly and you need to move away from your goals,” Procko says. To find bait that binds well to SARS-CoV-2, Procko and his colleagues removed thousands of substandard ACE2 copies using an experimental technique known as “mutagen. deep”.
So what is a deep mutation? Think of a Vegas slot machine – a combination of three different fruits equates to a certain payout (or not). DNA is similar: a trio of letters that code for a single amino acid, or protein building block. In this case, the team shuffled three-letter segments at 117 points in human DNA that previous studies showed affect how closely the coronavirus binds to the ACE2 receptor. This allowed researchers to essentially “pull the slot machine lever” to study how to swap each amino acid (one spin of the slot machine) for another acid that affected the receptor’s coronavirus bond. can be ACE2. In this case, the disturbed DNA is expressed in different versions of human cells in a lab dish.
“You can do a comprehensive test of many, many thousands of mutations, to see which ones are involved,” Procko said.
After creating cells with mutated ACE2 receptors – based on disordered DNA fragments – the researchers exposed the cells to the SARS-CoV-2 part to the ACE2 receptor, called is the receptor-binding region. They found that sACE2.v2.4 showed the highest affinity for the virus; The researchers then developed a version of the bait that could persist in the body without attaching to a cell, since the detachable receptor is all that is needed for a future drug.
Compared to an unmodified ACE2 receptor, “less than 1 percent of the entire protein chain has been altered” to produce lures, Proko notes. If fully developed as a treatment for humans, he said, the decoy receptors would be introduced into the body via injection or inhaled in the form of mist. He said drugs derived from living organisms, such as receptors for decoys, usually “last for a long time” and can stay in the body for a week or more.
A decoy receptor will serve a similar purpose antibody cocktail designed to treat COVID-19, which contains multiple antibodies that bind in different ways to SARS-CoV-2. However, a report was published June 15 in the journal Science Procko says viruses can mutate to escape the attachment of specific antibodies – a decoy receptor may be more reliable in the long run, since the virus will be less likely to mutate in a no longer binding manner. with ACE2, Procko said. The fact that sACE2.v2.4 strongly binds both SARS-CoV-2 and its precursor, SARS-CoV, supports this notion, as both viruses use ACE2 to break into cells.
Procko founded a startup called Orthogonal Biologics to continue working on the ACE2 lure earlier this year, together with study author Kui Chan, who takes on the CEO role. The next step is to do animal studies, and if the treatment goes to human studies, they have to show that the bait can be reliably produced on a large scale.
Interestingly, the anACE2 decoy developed by researchers attached to the Apeiron Biologics has been tested in clinical trials to treat COVID-19 and, to date, appears to be safe in both healthy individuals. strong and people with lung disease, according to a statement From the company. The main difference is that the existing decoy closely resembles the natural ACE2 receptor and is not mutated to bind as closely as possible to SARS-CoV-2, whereas sACE2.v2.4 does. (Procko and his colleagues were not involved in the design of the Apeiron decoy.)
Apeiron developed the existing decoy post-SARS as a coronavirus treatment, but has also tested the drug to treat various lung conditions, including acute respiratory distress syndrome (ARDS). and pulmonary hypertension. Based on the initial data, the patient appears to tolerate the treatment well, with no major side effects. Although the Apeiron product is different from the bait that Procko and his colleagues have developed, the early results are encouraging, says Procko. “We know you can give an injection [the Apeiron decoy] “Go to people and it doesn’t hurt them,” Procko said, “which gives hope to their mutant ACE2 lure.
Procko’s team has begun testing their bait on mice infected with COVID-19 and “has not observed any toxicity,” he noted.
First published on Live Science.