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ACE2 decoy irreversibly inactivates SARS-CoV-2, even antibody-resistant variants

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The ACE2 receptor as it appears on the surface of a cell, with SARS-CoV-2 spike proteins attached to it. The yellow layer is the cell membrane. Two identical ACE2 proteins associate and exist mainly outside the cell. They also pair up with two identical proteins called B0AT1, making the whole thing look much more stable.

I have to admit: I am very tired of COVID-19, stories about it and everything related to it. Enough already! I absolutely don’t like this topic. We all want to move on, even though COVID apparently doesn’t.

But I like to see an innovative approach that sticks to one disease, and that’s what we have here. Researchers from the Dana Farber Cancer Institute, Harvard University, Boston University, Colorado State University and Massachusetts General Hospital have developed a therapeutic protein that mimics the point of attack of SARS-CoV-2 – the ACE2 receptor – not only diverting the virus from actually binding ACE2 receptors, but irreversibly inactivating it. Discover it in free access on December 7 article in Scientists progress.

Vaccines are the first line of defense, of course, so stay up to date! I will always remember my first against COVID, at Gillette Stadium (even though I’m not really a Patriots fan). The fact that a huge urban community could come together and direct their resources and facilities for the common good like that really inspired me.

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But I’ve always felt that the best second line of defense against this thing was not so much to use antibodies, but to trick it into attaching itself to something it thinks is the ACE2 receptor, a protein that can normally be found emerging from the surface of human cells in lungs, heart, kidneys and intestine. This study shows the validity of this approach, but it also goes further.

It turns out that when the SARS-CoV-2 virus fully engages with a true ACE2 receptor, its spike protein ā€” which you see coming out of the virus in all those endless images of it ā€” undergoes an irreversible change that engages it to invade the cell but eliminates its additional ability to bind to an ACE2 receptor. The spike protein actually breaks down into two pieces, and the one that can attach to ACE2 is lost forever:

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The virus spike protein is made up of two parts, S1 (red) and S2 (grey). S1 is the part that actually attaches to ACE2 (blue). When it does, the spike protein undergoes a large and irreversible change, where S2 elongates and S1 is expelled. More S1 means the virus can no longer bind to ACE2.

If we could design an ACE2 decoy the right way, then maybe the virus would attach to it and be tricked into thinking it attacked a cell, and the spike protein would suffer the same irreversible break and couldn’t not go after more cells. The more spike proteins we could knock on a virus particle, the lamer it would become:

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On the left, an active virus particle with functional spike proteins sticking out. On the right, what the same particle (i.e. toast) will ideally look like after exposing it to an ACE2 decoy

Going into this research, this was one aspect that was unclear. Would an ACE2 decoy be able to not only attach to the virus, but also trick it into inactivating itself in practice?

If so, we would have a few key advantages over antibodies.

Therapeutic antibodies against SARS-CoV-2 are also directed against the spike protein, which makes perfect sense because that’s what you want to interfere with, so the virus can’t attack your cells. But the antibodies attach to the spike protein in the random way they end up doing so, not by mimicking ACE2. So, although a garden variety antibody sticks perfectly to the virus, it will not cause this irreversible and disabling change because the virus does not think it has found an ACE2; he just thinks he has a big piece of gum stuck to his face.

The other thing is that the spike protein evolves rapidly, so an antibody that works very well on one variant could work poorly on a new variant. We have certainly seen this in practice. Omicron, for example, is quite resistant to a number of antibodies that worked on older variants like Delta, because Omicron’s spike protein has evolved a lot; he has more than 30 mutations in it! So those old antibodies don’t recognize it anymore. Even Paxlovid, a small molecule antiviral, is lose its grip also on the new variants.

But no matter how much a virus changes, its spike protein must better retain its ability to stick to human ACE2. If not, this virus goes straight into the evolutionary trash can. So if we can design a decoy that looks like ACE2 for the virus and also has good stability and security in the body then we will have a weapon that works against everything SARS-CoV-2 variants, new and old, however they evolve, and indeed even against other nasty coronaviruses that may arise in the future.

OK so what does a good ACE2 lure have to have? It’s necessary…

  1. Looks a lot like ACE2 so that all viral variants recognize it and want to pursue it
  2. Be free to float, don’t get attached to cells like the real ACE2
  3. Have a reasonably long life in the body
  4. Being able to penetrate tissue where the virus may be hiding
  5. Avoid having the blood modifying functions of the real ACE2, so we’re not exaggerating
  6. Do not cause an apocalypse of the immune response in the patient

Part 1 is quite simple. We know what ACE2 looks like when it’s in place and working on the surface of a cell (see main log image). So we have to keep the part that sticks to the tip protein intact. The main question is how much should we keep? The authors tried a few different things there, and honestly, it’s a bit of trial and error. But in the end, they found it worked better when they kept more of the ACE2 protein, even the parts that the spike protein doesn’t attach to.

We can actually hit parts 2, 3, and 4 at the same time by combining our ACE2 decoy with the bottom half of an antibody (its ā€œFcā€ region). This configures our decoy to behave like a conventional antibody, except with its commercial end designed by us. Here’s how a natural antibody compares to this “Fc fusion” we’re going to create:

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Note that the doubled structure of the Fc region gives us two ACE2 decoys side by side, just like ACE2 appears on an actual cell surface. Prime!

Like any other antibody, this Fc fusion decoy will be soluble, it hang out for some time, and it will be able to penetrate most tissues, even the placenta.

Part 5 is not too difficult. The important job of ACE2, when not commandeered by viruses, is to alter hormones that regulate blood pressure. So unless there’s a benefit to changing that, which has never been demonstrated, we’d rather not mess with it by adding a ton of active ACE2s everywhere. Luckily, all we have to do is change two amino acids in our ACE2 decoy to make it inactive while retaining its ACE2-like structure.

And part 6, the immune apocalypse! When an antibody sticks to something, its Fc region can attract a gallery of immune system rogue cells to attack said thing:

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In the center, the unfortunate target. When antibodies (the green Y-shaped things) with active Fc components bind to them, some monsters appear, and there’s a little harm

But again, in the spirit of not messing around too much, the authors modified Fc (again with two specific amino acid changes) so that it doesn’t have this ability. That’s not to say it’s necessarily the best choice; others left Fc alone and let it be active in their Fc fusion designs. The question is, do we want to encourage an inflammatory response in a patient who already has a lot of inflammation from COVID-19? So I would say I agree with the authors here that we should put active Fc on the back burner. Let’s just entrain the virus particles and leave it at that for now.

So how did the ACE2 lure work? First, in human cells, it neutralized the “original” SARS-CoV-2 (WA01/2020) very well, as did a panel of common anti-COVID therapeutic antibodies (sotrovimab, cilgavimab, tixagevimab, casirivimab and imdevimab). But against Omicron, all of those others lost a lot of their potency, as the FDA also observed and warned about, but the ACE2 lure actually won Powerful. The lure has been shown to attach effectively to Alpha, Beta, Gamma, Delta, Epsilon, and Omicron variants.

It also had a respectable half-life in hamster blood serum of 52 hours. It’s not as good as a real antibody, but it’s not bad either.

And the answer to the other big question – can the ACE2 decoy cause the spike protein to change irreversibly like the real ACE2? – was yes. The decoy has been shown to cause the S1 and S2 components of the spike protein to separate, more so at higher doses, and not at all when no decoy is added.

Clinical trials are therefore next, and here we have reason to be optimistic. From 2020, there was 13 Fc-fusion type FDA-approved drugs, so it’s not like we’re in uncharted waters. We know this approach can be safe and effective, and we hope this one will follow the same trajectory.

As always, I don’t want to say that this is the only group studying this or that they’re going to solve all the world’s problems on their own, but I just want to give an overview of what’s going on in this area , of what Think is, and where it seems to be going.

But if it succeeds, we will have an approach that is no longer subject to the whims of a mutating virus, but instead places a trap at the only door the virus can use to enter. And that will give us a blueprint to help be better prepared against future viral pandemics. Silver lining!


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