The ACE2 decoy irreversibly inactivates SARS-CoV-2, even antibody-resistant variants
The ACE2 decoy irreversibly inactivates SARS-CoV-2, even antibody-resistant variants
I have to admit: I did very tired of COVID-19, stories about it and everything related to it. That’s enough! I’m not enjoying this thread at all. We all want to move on, even if the COVID seems to be does not work.
But I like to see an innovative approach that ties it to the disease, and that’s what we have here. Researchers at the Dana Farber Cancer Institute, Harvard University, Boston University, Colorado State University and Massachusetts General Hospital have designed a therapeutic protein that mimics the point of attack of SARS-CoV-2 – the ACE2 receptor – not only deters the virus from binding to the real ACE2 receptors, but irreversibly inactivates it. Check it out in open access on December 7th article in Scientific progress.
Of course, vaccines are the first line of defense, so stay up to date! I’ll always remember my first against COVID, at Gillette Stadium (even though I’m not much of a Patriots fan). The fact that a huge urban community can come together and direct its resources and content for the common good was truly inspiring to me.
But I’ve always thought that the best second line of defense against this thing isn’t so much using antibodies, but rather tricking it into binding to what it thinks is the ACE2 receptor, a protein that can usually be found sticking out of the surface of human cells in lungs, heart, kidneys and intestines. This study demonstrates the validity of that approach, but also goes one step further.
It turns out that when the SARS-CoV-2 virus fully binds to the right ACE2 receptor, its spike protein — which you see sticking out of the virus in all those endless pictures of it — undergoes an irreversible change that commits it to invading cells, but eliminates its further ability to bind to the ACE2 receptor. The spike protein actually breaks into two parts, and the one that can attach to ACE2 is lost forever:
If we could design the ACE2 decoy just right, maybe the virus would latch on to it and be tricked into thinking it had invaded the cell, and the spiked protein would undergo the same irreversible decay and be unable to move further into the cell. The more spiky proteins we can hit on a viral particle, the more it would become lamellar:
Going into this research, this was an aspect that was not clear. Could the ACE2 decoy not only attach to the virus, but also trick it into inactivating itself in practice?
If so, we would have several key advantages over antibodies.
Therapeutic antibodies against SARS-CoV-2 also target the spike protein, and that makes perfect sense because that’s what you want to interfere with, so the virus can’t attack your cells. But the antibodies bind to the spike protein in whatever random way they end up, not by mimicking ACE2. So while the antibodies from the garden will stick to the virus just fine, they won’t cause this irreversible and disabling change because the virus doesn’t think it has found ACE2; he just thinks he has a big piece of chewing gum stuck to his face.
Another thing is that the spike protein evolves quickly, so an antibody that works well against one variant may do poorly with a new variant. We have definitely seen that in practice. Omicron, for example, is quite resistant to many antibodies that worked against older variants like Delta, because Omicron’s spike protein has evolved a lot; have more than 30 mutations in it! So those old antibodies no longer recognize it. Even Paxlovid, a small molecule antiviral drug losing his grip and on newer versions.
But no matter how much the virus changed, its spike protein would better retain its ability to stick to human ACE2. If not, that virus goes straight into the evolutionary trash. So if we can design a decoy that looks like ACE2 for the virus and also has good stability and safety in the body, then we will have a weapon that works against all variants of SARS-CoV-2, new and old, no matter how much they have evolved, and even against other nasty coronaviruses that might appear in the future.
Well then, what should a good ACE2 bait have? You have to…
- It closely resembles ACE2 so all viral variants recognize it and want to follow it
- Be free to float around rather than being attached to the cells like the real ACE2
- Have a reasonably long life in the body
- Being able to penetrate tissues where the virus may be hiding
- Avoid the effect of real ACE2 on the blood change, so that we do not overdo it
- It does not cause an apocalypse of the patient’s immune response
The first part is quite simple. We know what ACE2 looks like when it’s in place and running on the cell surface (see main log image). So we have to keep the part that sticks to the protein spike 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 they eventually found that it worked better when they kept more of the ACE2 protein, even the parts where the spike protein didn’t bind.
We can actually hit parts 2, 3, and 4 all at once by combining our ACE2 decoy with the bottom half of the antibody (its “Fc” region). This sets up our decoy to behave like a conventional antibody, except with the business objective we designed. Here’s how the natural antibody compares to this “Fc fusion” we’re going to make:
Like any other antibody, this Fc-fusion decoy will be soluble, it will be hangout some time, and will be able to penetrate most tissues, even the placenta.
The fifth part is not too difficult. An important task of ACE2, when not under viral control, is to modify hormones that regulate blood pressure. So unless there’s some benefit to changing it, which has never been proven, we’d rather not play with it by adding a ton of active ACE2 all over the place. Fortunately, all we have to do is change two amino acids in our ACE2 decoy to render it inactive but still retain its ACE2-like structure.
And part 6, the immune apocalypse! When an antibody sticks to something, its Fc region can attract a rogue gallery of cells from the immune system to attack that thing:
But again, in the spirit of not messing around too much, the authors tweaked the Fc (once again with two specific amino acid changes) so that it doesn’t have this ability. I’m not saying it’s necessarily the best choice; other left Fc alone and let it be active in their Fc-fusion designs. The question is, do we want to stimulate an inflammatory reaction in a patient who already has a lot of inflammation due to COVID-19? So I would say that I agree with the authors here that we should put active Fc on the back burner. Let’s just limp the virus particles and leave it at that for now.
So how did the ACE2 lure perform? First of all, it neutralized the “original” SARS-CoV-2 in human cells (WA01/2020) very well, as well as 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 power, as the FDA also noted warned oh but ACE2 bait actually gained potency. The bait has been shown to bind 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 an ACE2 decoy cause an irreversible change in the spike protein like real ACE2 can? – whether. The decoy was shown to cause the S1 and S2 components of the spike protein to separate from each other, even more so at higher doses, and not at all when no decoy was added.
So clinical trials are following, and here we have reason for optimism. From 2020 there were some 13 FDA-approved Fc-fusion drugs, so it’s not like we’re in uncharted waters. We know that this approach can be safe and effective, and we hope that this one will follow the same trajectory.
As always, I don’t mean to imply that this is the only group studying this or that they will solve all the world’s problems on their own, but I just want to give a hint of what’s going on in this field, what they’re thinking, and where it seems to be going.
But if successful, 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 through which the virus can enter. And it will give us a blueprint to help us be better prepared against future viral pandemics. Silver lining!
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