There are decoys that may trick COVID-19 to protect humans from infection

Last Updated 21 August, 2020. Cellspect Co., Ltd.

In the ravages of Covid-19, scientists from all over the world try hard to find an effective treatment as soon as possible. So far, we know that the coronavirus infects cells by plugging into a receptor on their surface. Now, by crafting a "decoy" of that receptor, scientists aim to foil the virus's attack. [1]

In a new study, published Aug. 4 in the journal Science, researchers engineered such a decoy and found that the coronavirus bound tightly to the imposter receptor, and once attached, the virus couldn't infect primate cells in a lab dish. [2] The decoy binds to the virus as tightly as a neutralizing antibody, a Y-shaped molecule generated by the immune system to grab the virus and prevent it from infecting cells.

 

This research team found that their newly designed decoy, known as sACE2.v2.4, tightly binds both the novel coronavirus SARS-CoV-2 and SARS-CoV. The research is still in very early stages and no decoy receptor has ever been approved as a treatment for an infectious disease. “If the decoy works in animals as it does in cell culture, it could be developed into a COVID-19 treatment and preventative therapy for humans” the study author Procko said. "This would be something new for being the first decoy approved as an antiviral, if it is successful.”

A few decoy receptors have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of inflammatory- and immune system-related diseases, such as the rare "familial cold autoinflammatory syndrome" that causes recurrent fevers, joint pain and inflammation of the eyes. [3] However, decoy receptors developed as antiviral treatments have historically hit roadblocks on their way to approval.

Procko noted that, to be a successful antiviral, a decoy receptor must meet two major criteria: 

First, it must not disrupt important bodily functions, given that natural receptors often play multiple roles in the body. For example, the ACE2 receptor, which COVID-19 exploits as a gateway into cells, also helps control blood volume and lower blood pressure, he said. By infecting cells with ACE2 receptors, COVID-19 actually interferes with ACE2 activity in the body — a decoy ACE2 receptor could potentially "rescue" some of this lost activity by leaving natural receptors open for business, rather than bound to the coronavirus, Procko said.     However, decoy ACE2 receptors could cause unanticipated side effects, so the researchers need to monitor for these in animal studies and early clinical trials, he added. 

In addition to being safe to administer, a decoy receptor must show high affinity for the virus it targets, meaning it binds tightly to the virus in human cells. "To be a good binder, with high affinity, you need to bind on your target quickly and you need to come off your target slowly," Procko said. To find a decoy that binds well to SARS-CoV-2, Procko and his colleagues ruled out thousands of inadequate ACE2 copycats using an experimental technique known as "deep mutagenesis." In this case, the team scrambled the three-letter segments in 117 spots in human DNA that past studies suggested affected how tightly coronavirus bound to the ACE2 receptor. This allowed the researchers to study how swapping out each amino acid for another affected the ACE2 receptor's coronavirus binding. 

After producing cells with mutant ACE2 receptors — ones based on scrambled DNA segments — the researchers exposed the cells to the portion of SARS-CoV-2 that locks into the ACE2 receptor, known as the receptor-binding domain. They found that sACE2.v2.4 showed the highest affinity for the virus; the researchers then developed a version of the decoy that can exist in the body without being attached to a cell, as the detached receptor is all that would be needed for a future drug.

Compared with an unmodified ACE2 receptor, "less than 1% of the entire protein sequence has been changed" to craft the decoy, Proko noted. If fully developed as a treatment for humans, the decoy receptor would likely be delivered into the body through an injection or inhaled as a mist, he said. Drugs derived from living things, like the decoy receptor, are "frequently long-lived," and can persist in the body for a week or more, he said.

 

 A decoy receptor would serve a similar purpose to antibody cocktails designed to treat COVID-19, which would include multiple antibodies that bind in different ways to SARS-CoV-2. However, a report published June 15 in the journal Science suggests that the virus can mutate to escape the grasp of specific antibodies. [4] “A decoy receptor might be more reliable in the long run, as the virus would be less likely to mutate in such a way that it no longer binds to ACE2” Procko said. The fact that sACE2.v2.4 tightly binds both SARS-CoV-2 and its predecessor SARS-CoV supports this notion, given that both viruses use ACE2 to break into cells. 

The next step of this research is to do animal studies, and should the treatment advance to human studies, they have to show the decoy can be manufactured reliably at large scales. Procko's team has begun testing their decoy in mice infected with COVID-19 and has "not yet observed any toxicity," he noted.

 References:

  1. Nicoletta Lanese, Aug 12, 2020. “Decoys could trick COVID-19, keep humans safe from infection” Live Science press

  2. Kui K. Chan et al., Aug 04 2020 “Engineering human ACE2 to optimize binding to the spike protein of SARS coronavirus 2” Science. DOI: 10.1126/science.abc0870

  3. Cecilia Garlanda et al., July 09, 2013 “Decoys and Regulatory “Receptors” of the IL-1/Toll-Like Receptor Superfamily” Front Immunol. 4: 180.

  4. Alina Baum et al., June 15 2020 “Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies” Science. DOI: 10.1126/science.abd0831

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