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Scientists demonstrate how COVID-19 infects human cells

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Researchers have used cryogenic electron microscopy to show that coronaviruses enter human cells through an interaction with angiotensin-converting enzyme 2 (ACE2).

coronavirus with cell surface protein projections

Scientists exploring how coronaviruses like COVID-19 infect human cells have shown that the SARS-CoV-2 spike (S) glycoprotein binds to the cell membrane protein angiotensin-converting enzyme 2 (ACE2) to enter human cells.

COVID-19 has been shown to bind to ACE2 via the S protein on its surface. During infection, the S protein is cleaved into subunits, S1 and S2. S1 contains the receptor binding domain (RBD) which allows coronaviruses to directly bind to the peptidase domain (PD) of ACE2. S2 then likely plays a role in membrane fusion.

Chinese researchers have now used cryogenic electron microscopy (cryo-EM) to study the structure of the ACE2 when it is bound to one of its typical ligands, the amino acid transporter B0AT1 and also how the COVID-19 RBD may bind to the ACE2-B0AT1 complex. These structures have previously not been identified and could aid in producing antivirals or a vaccine that can block coronavirus infection by targeting ACE2.

The paper, published in Science, suggests ACE2 needs to dimerise to be active. The resultant homodimer has two PDs, able to bind two COVID-19 S protein trimers simultaneously.

A previous study found COVID-19 S proteins form trimers with two of the RBDs facing one direction (down) and the other facing the opposite way (up).

COVID-19 S protein trimer structure showing the two 'down' receptor binding domains in grey and single 'up' domain in green

Side and top views of the pre-fusion structure of the COVID-19 S protein with a single RBD in the up conformation. The two RBD-down protomers are shown as cryo-EM density in either white or grey and the RBD-up protomer is shown in ribbons coloured green (credit: adapted from Wrapp, D, et al.).

In the current study, the team identified that the structures could only bind if the PD interacts with the up RBD.

protein structure diagram of SARS-CoV binding domain interacting with ACE2-B0AT1 complex

The overall structure of the RBD-ACE2-B0AT1 complex. (A) Cryo-EM map of the RBD-ACE2-B0AT1 complex. Left: Overall reconstruction of the ternary complex at 2.9 Å. Inset: focused refined map of RBD. (B) Overall structure of the RBD-ACE2-B0AT1 complex. The complex is coloured by subunits, with the protease domain (PD) and the Collectrin-like domain (CLD) coloured cyan and blue in one of the ACE2 protomers, respectively. The glycosylation moieties are shown as sticks (credit: Yan, R et al.).

They further compared how SARS-CoV-2-RBD binding is different to other SARS-CoV-RBDs binding; showing that some changes in the sequence may make associations tighter in COVID-19, while others could reduce the binding affinity.

The researchers concluded that their research could contribute to structure-based designs of decoy ligands or antibodies able to specifically target ACE2 or coronavirus spike proteins to prevent viral infection.

46 responses to “Scientists demonstrate how COVID-19 infects human cells”

  1. trueman says:

    thats some awesomely exciting research.i love virology!!!!

    • Patrick Walsh says:

      We know from TCM, and indeed conventional research, that a colon-lung axis exists in the human body. I wonder, in those severely ill people requiring ventilation, if there is defective communication between the colon and the lung, which if identified and corrected, could allow the immune system to properly deal with the threat of Covid-19??

  2. dev says:

    What if we could prevent the rbd’s from getting binded up by changing the shapes of the receptors ? so that the corona doesnt even recognize it ?

    • CT says:

      It is not only the shape that matters at molecular levels, but chemical signalling also, especially in the recognition context.

      • Majid says:

        Can ARB agents change the number of ACE receptors in epithelial side ?
        Is ACE receptor gene type on the affinity of virus on receptor ?

        • Subhradip says:

          Ang2 receptor AT1 and ACE2 interacts to form a complex in absence of Ang2. This makes sure that all ACE2 is occupied and not available or SARS-CoV2 entry. ARBs ( .. tans)does the same thing in that it prevents Ang2 interacting with AT1 thus stabilizing AT1 -ACE2 complex , thus also preventing virus entry

    • Juliet Makinia says:

      Let’s try

    • vanessa87 says:

      I think that Zn ion cause such a change in the shape of ACE2. That’s why supplements with Zn are supposed to lessen the duration of cold symptoms.

  3. mark says:

    so do ACE 2 inhibitors block the same region and is there any mitigation of inflammatory response?

    • mohammad says:

      When ACE 2 inhibitors like in some antihypertensive medications are on board they do INCREASE the number of ACE2 sites on the cells and may have a facilitation effect to the benefit of the virus, that is why symptoms are worse when the patient with co-morbid hypertension and already are on Ace2 inhibitor. However no strict recommendation so far to discontinue Ace2 inhibitors in patients affected with COVID-19
      This is from UpToDate just few days ago:
      “Patients receiving ACE inhibitors/ARBs — Patients receiving angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) should continue treatment with these agents. This approach is supported by multiple guideline panels [138-142].

      There has been speculation that patients with COVID-19 who are receiving these agents may be at increased risk for adverse outcomes [143,144]. Angiotensin-converting enzyme 2 (ACE2) is a receptor for SARS-CoV-2 [145,146], and renin-angiotensin-aldosterone system inhibitors can increase ACE2 levels. Although patients with cardiovascular disease, hypertension, and diabetes may have a more severe clinical course in the setting of infection with SARS-CoV-2, there is no evidence to support an association with these agents. In addition, stopping these agents in some patients may exacerbate comorbid cardiovascular or kidney disease and lead to increased mortality [147].”

      • Bart says:

        We must distinguish ACE inhibitors and ARB blockers, although they have similar effects. Don’t ARBs support COVID by revealing very active ACEs? Perhaps ACE inhibitors rather preventing infection.

  4. Arash._.rezae says:

    hi every body what if we can replace some other things that have similar structures like human cells Ace 2 with Ace 2 that allow us bind covid 19 with that instead of human cells ace 2 ‘s .
    this work’s for healing sick people but not immune them for long period of time

    • Raima says:

      I was thinking of the same thing, a compound that holds the similar structure as ACE 2 receptor and has more stronger affinity.

  5. Philip Borin says:

    Try to use an ACE2 selective inhibitor like MLN-4760 wich have to be effective against that virus by blockage of his key attacked receptor.

    • Bob O says:

      Losartan is promising and actually exhibits pretty fair efficacy in prophylactically blocking SARS-2-CoV-2 and MERS but, most patients with respiratory infections (bac-t or viral) may present in the E.R. with moderate to severe hypotension… we can stop the viral docking… but, unfortunately kill the patient.
      Interesting sidebar would research Seattle area nursing homes and assess surviving patients for data on losartan (or other ACE2 receptor inhibitor) Rx’s versus angiotensin production inhibition- Lisinopril, et al)
      Hypothesis would propose correlation of elderly survivors using receptor complex (blocking) competitive inhibition: Losartan dosing prior to viral exposure.

    • Bob O says:

      https://www.ncbi.nlm.nih.gov › pub…
      Angiotensin receptor blockers as tentative SARS-CoV-2 therapeutics.

      by D Gurwitz · 2020
      Mar 4, 2020 · Angiotensin receptor blockers as tentative SARS-CoV-2 … angiotensin receptor 1 (AT1R) blockers, such as losartan, as … that the angiotensin-converting enzyme 2 (ACE2) very likely …

      (Various other workers investigated this; 2002-ish and on.)

  6. Philip Borin says:

    Btw ethanol dimish B0AT1’s synthesis and in that way it can diminish the action of the virus by disturbing the ACE2-B0AT1 complex

  7. hicbousl says:

    what if they injected decoy cells that had the same structural make-up of cells that just activated when a covid attached and just engulfed it.

  8. Lets try to change the shape of the two structures that the active site doesn’t recognize it

  9. Chuck says:

    Losartan and other ARB’s block ACE2 receptors. Although it targets smooth endothelial cells in blood vessels mainly, it still has affinity for lung ACE2 I believe.

  10. R.Karwal says:

    What is the size of the virus COVID- 19 cell. If it is 400/500 microns (?) it is very big
    comparison to other Cronoviruses.

  11. Worryingly ACE2 inhibitors (blood pressure medicines) may increase morbidity: https://www.thelancet.com/pdfs/journals/lanres/PIIS2213-2600(20)30116-8.pdf

  12. Is COVID 19 extracellular initially until it begins to infect the cells of the lung membrane when it then becomes intercellular.

  13. C.F. KOO says:

    S1 of CONVID-2019 may be synthesized artificially and used to block the ACE2 to previde further infaction when the early human infaction happened. As the molecular size is so small that it would be easy to reach to the target cells.

    • Raima says:

      I was telling it to my friend last night, about the substitute of S1 subunit and to make a compound that holds more affinity towards it than the ACE 2 receptor.

  14. Irina says:

    Hi,
    It is posible that an angiotensine II receptor blocker/antagonist act as inhibitor to prevent coupling of covid S proteine the ACE II enzyme?

  15. Jasonn says:

    Would people taking ACE inhibitors for blood pressure have any less or greater chance of infection?

  16. Brahmaiah Pendyala says:

    Is there any aromatic compounds that have binding affininity toward RBD of virus?
    Those compounds can neutralize virus

  17. anil says:

    can there be a correlation between blood pressure and covid19-ace2 binding ? can diuretics decrease the bindings ?

  18. Kashish says:

    What if we can breaks its protein present in rna so its functions turn over but how its big question….

  19. A very big challenge is ahead for Virology / Immunology scientists and to help pharmacology to develop vaccine as well treatment medicine against this deadly COVID-19.

  20. Brahmaiah Pendyala says:

    In silico screening (using homology modeling of RBD domain of spike protein followed by molecular docking) of edible volatile aromatic compounds library is a faster method to select the compounds that show binding affinity towards covid-9. These compounds can bind and neutralize the virus. Since they’re natural edible compounds, no need for further clinical trials, consumption also easy via inhalation.

  21. Jean Paul Zoghbi says:

    Nitrofurantoin, an antibiotic that is used to treat urinary tract infections, has a chemical structure that can bind on the Coronavirus S-protein / ACE2 receptor and can potentially disrupt host/virus interface

  22. Andy says:

    So what aromatic compounds are you talking about?

  23. bill maynard says:

    we need to study metformin as a carrier substance with ACE inhibiters.

  24. KV says:

    Cell regulation. Sadly overlooked.
    Among the alkaloids present in the noni plant already identified, Heinicke (1985), found considerable amounts of the xeronine precursor, the proxeronine. According to the author, xeronine acts in the transformation of the molecular structure of proteins, thus presenting a wide range of functions and biological activities, since in a situation where a protein, enzyme, or a cellular signal receptor is not in its proper configuration, xeronine will promote the rearrangement of the molecular structure to its active conformation. Moreover, according to Sang et al. (2002), the presence of xeronine allows NFJ to have a number of

  25. Mohit agrawal says:

    what if we can neutralize the surface receptors which are responsible for binding with human cell?
    somehow we can inactivate the enzyme production?

  26. claudio says:

    Why don’t use Efavirenz o Riluzole that are a lot of electronegative

  27. Raima says:

    People who recovered might possibly have developed antibody against COVID-19, couldn’t their plasma be extracted to make an antidote or vaccine out of it?

  28. awais says:

    i think a drug that bind to an s protein and prevent it from binding to receptor will prevent the attachment and entry of virus

  29. Rachelle says:

    Maybe there is a protein that can counteract with ACE2. A protein that counteracts with ACE2 can prevent ACE2 from actually allowing the spike cells from the coronavirus from entering ACE2. If we can find a protein that counteracts with ACE2, the spike cells from corona will have absolutely nothing to infect, because the spike cells cannot enter/infect human cells.
    It is great that we’ve already found a source of how the coronavirus enters the body-through ACE2. Now I think the answer is finding another protein that can make ACE2 die out when it recognizes the spike proteins entering the cell. Making drugs that can bind to certain proteins can be dangerous, and can have long term effects to a person’s body. This is why I think finding, or even making a protein that makes ACE2 die out when it recognizes spike proteins would be a better answer. This can probably be made an injection.

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