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  • Writer's pictureGary Birnbaum, MD

A novel but possible approach for preventing COVID-19

Paper #1: De novo design of picomolar SARS-CoV-2 miniprotein inhibitors

Longxing Cao, Inna Goreshnik, Brian Coventry, et al.

Science 370, 426–431 (2020)

Paper #2: De novo design of potent and resilient hACE2 decoys

to neutralize SARS-CoV-2

Thomas W. Linsky, Renan Vergara, Nuria Codina, et al.

Science 370, 1208–1214 (2020)

Bottom Line:

Vaccines are essential to control the coronavirus pandemic. However, vaccines have two inherent shortcomings. First, their effectiveness relies on a recipient’s well-functioning immune system. Second, their effectiveness can change if their target virus also changes due to mutations. Highly specific monoclonal antibodies also are used as a treatment for viral infections. Their effectiveness too can change if their target virus mutates.

Persons with MS on disease-modifying therapies have altered immune systems, possibly diminishing their responsiveness to vaccines. In addition, the coronavirus SARS-CoV-2 that causes COVID-19 is mutating. If these mutations affect key portions of the virus, treatments other than vaccines and antibodies may be needed for effective disease control. The papers listed above suggest alternative approaches to preventing infection with SARS-CoV-2. These approaches do not require activation of the immune system. Rather they involve administration of proteins that interact directly with the virus’ spike proteins, proteins that are essential for the virus to attach to and enter into a cell. These methodologies are not yet tested in humans and are a long way from clinical use. However, they represent a novel and potentially powerful approach to the control of SARS-CoV-2 infection. For now, vaccination, masks, social distancing and hand washing are still the best ways to avoid disease.

Key Points:

1. Vaccines induce resistance to disease by stimulating an individual’s immune system. This results in the production of protective antibodies and protective immune cells.

2. If a person’s immune system is diminished or otherwise impaired, protective immunity may be compromised.

3. There are no data to suggest that the immune systems of persons with MS are deficient in their response to SARS-CoV-2, the coronavirus that causes COVID-19. However, persons with active relapsing forms of multiple sclerosis may be on potent disease-modifying therapies that exert their beneficial effects by reducing or altering that individual’s immune system. As a result, protective immune responses to anti-SARS-CoV-2 vaccines may be diminished.

4. Antibodies, in particular monoclonal antibodies (antibodies that are highly specific and tightly binding) are used to treat COVID-19. They are effective as long as the viral proteins they attach to don’t change. Unfortunately, in an effort to survive viruses mutate or change.

5. While most viral mutations do not affect the ability of the virus to infect or to cause more severe disease, such mutations can occur, greatly reducing the effectiveness of both vaccines and monoclonal antibodies. As of this writing, such resistance to vaccines and antibodies have not been noted with current strains of SARS-CoV-2. However, this could change.

6. The above two papers describe approaches to the prevention and treatment of SARS-CoV-2 infection that are not dependent on either activating a person’s immune system or on neutralizing the virus with antibodies. The approaches are based on the following principles.

7. The SARS-CoV-2 virus enters our bodies through the nose and mouth (the upper respiratory tract). Once there it attaches to cells and penetrates them by latching on to a protein on the surfaces of cells called “angiotensin converting enzyme 2” or ACE2. The virus proteins that latch on to ACE2 are on the spike of the virus and are called the “receptor binding domain” or RBD.

8. Using artificial intelligence (AI) programs the two papers were able to determine the shape of the human ACE2 receptor and the shape of the viral RBD. With this information the researchers were able to design and synthesize small proteins that tightly bound to the viral RBD, preventing the virus from attaching to and entering cells.

9. The authors of Paper #1 were able to design multiple small proteins they called “miniproteins.” They tested the effectiveness of the miniproteins to prevent infection of cells in tissue culture that expressed the ACE2 receptor. The miniproteins bound so tightly to the viral RBD that the tissue culture cells were protected from infection. Indeed, these miniproteins were six times more effective in preventing infection than the most potent anti-viral antibodies they tested.

10. Miniproteins are much smaller than antibodies and thus can find their way to attach to more than 20 times the number of RBD neutralizing sites than could the large antibody molecules.

11. The authors also felt that, since multiple miniproteins attached to the virus’ RBD at multiple sites, it would be highly unlikely that any single mutation in the virus’ RBD would allow the virus to “escape” being neutralized by the miniproteins.

12. Most importantly, the miniproteins were easily and inexpensively produced and were stable at room temperature. The authors also noted that while immune responses to the miniproteins could occur, this would be unlikely given their small size.

13. The scientists of Paper #2 used similar approaches to design proteins that were ACE2 decoys and competed with cell surface ACE2 receptors for binding to SARS-CoV-2 RBDs. From an initial sample of 35,000 proteins they found two extremely potent inhibitors or decoys. They were careful to avoid making inhibitors that might prevent the normal activity of ACE2 on cells surfaces and chose protein shapes that would make it very unlikely, but not impossible, for mutations to allow the virus to “escape” being neutralized by these proteins.

14. Similar to the findings noted in Paper #1, the scientists showed that their synthesized decoys were able to prevent tissue culture cells from being infected with SARS-CoV-2. They also showed that administration of these decoys into the upper respiratory tracts of hamsters 12 hours before infection with lethal doses of SARS-CoV-2 gave 100% protection to the animals.

15. The successful development of small proteins that block the ability of viruses such as SARS-CoV-2 to infect cells, without the need for activation of a person’s immune system, could be a breakthrough in controlling the coronavirus pandemic.


Vaccines, antibodies and immune cells are powerful tools to treat viral infections. But as noted above they require the presence of an intact immune system and the relative stability of the target virus. Vaccines are also expensive to produce, require complex manufacturing procedures, and can require, as for the Pfizer and Moderna vaccines, freezing storage temperatures.

Artificial intelligence or AI programs have been used in multiple ways during the current coronavirus pandemic. They assist in contact tracing, are used to model rates of infection, and also to determine if any currently available and approved drugs can be “repurposed” as treatments for COVID-19.

The above two papers represent novel approaches to the treatment of viral infections that avoid many of issues noted above with vaccines and immunologic reactions. Both papers describe the use of artificial intelligence (AI) programs to determine the configurations or shapes of the proteins the SARS-CoV-2 virus uses to attach itself to cells (ACE2) as well as the configurations or shapes of the receptor the virus uses to attach to ACE2 (the viral receptor binding domain or RBD). Both groups then used this information to design small proteins that bound to the viral RBD and in so doing competed and inhibited the virus binding to the cell’s ACE2.

The proteins bound with very high strength or affinity, were stable at room temperature, and were inexpensive to produce. Most importantly, since they were much smaller than anti-viral antibodies, they were able to stick to or bind to multiple sites on the viral RBD, making it much less likely that the virus could quickly mutate or change to escape being neutralized. Indeed, if the virus were to mutate such that the protein inhibitors no longer bound to the RBD, the virus could lose its ability to infect cells.

Both groups of investigators showed that addition of their miniproteins or decoys prevent SARS-CoV-2 from infecting cells in tissue culture. The scientists of Paper #2 showed that pretreatment of hamsters with their “decoys” offered 100% protection from lethal doses of the virus. Both groups noted that work in humans will begin.

While there are clear advantages to the use of small protein viral inhibitors, there are at least 4 possible concerns related to their use. First is that their effectiveness is not long lasting and may require daily direct administration into the upper respiratory, probably via a nasal spray. Thus, compliance with daily administration will be essential but could be a barrier to use. Second, since the inhibiting proteins are “foreign” proteins, it is possible that individuals could make immune responses to the proteins, neutralizing their effectiveness. The authors of Paper #1 note that the small size of their miniproteins makes this unlikely but could still happen. The third possible issue is that the presence of these inhibitors or decoys could prevent the normal function of ACE2 in the body, causing ill effects. The fact that the inhibitors are designed based on their abilities to bind to the viral RBD and not on their similarity to cellular ACE2 makes this possibility less likely. Finally, in order to be effective, the inhibitor proteins need to be administered at the sites of initial coronavirus entry into the body, namely the upper respiratory tract. However, once infected, the virus spreads into the lungs and lower respiratory tract as well as to other organs. Thus, use of miniproteins and protein decoys most likely would have no effect once the virus has spread beyond the upper respiratory tract.

It’s obvious that a great more work needs to be done before small protein inhibitors or receptor decoys against SARS-CoV-2 binding become available. However, their low cost, stability, absence of a need for an intact immune system and high possible potency makes these biologicals a potentially breakthrough therapy for controlling the coronavirus pandemic.

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