The SARS-CoV-2 Virus, the ACE2 Receptor, and the APN01 Drug

Coronavirus structure

Structure of a coronavirus (Photo by Scientific Animations/Wikipedia, CC BY-SA 4.0 license)

Scientists seem to be progressing in their understanding of the structure and behaviour of the SARS-CoV-2 virus, which causes the coronavirus or COVID-19 infection that is currently of concern. The progression is very important because understanding the nature of the virus may enable a treatment to be discovered.

The information given below describes some relevant research from the University of British Columbia and the Karolinska Institute in Sweden. It’s not a description of a cure for the infection. It does describe some aspects of the biology of the virus as well as a chemical that might be helpful in reducing the viral load, however. As in the other treatments that are being investigated, researchers don’t yet know whether the chemical will be helpful, but their research could be useful.

A virus isn’t a cellular organism. It consists of a strand of DNA or RNA covered by a coat of protein known as a capsid. In some viruses, a lipid envelope covers the protein. A coronavirus has RNA and a lipid envelope. It also has protein spikes that extend through the envelope. The longest ones remind scientists of the sun’s rays and gave the entities their name.

Unlike cells, viruses can’t reproduce on their own. They must hijack the “machinery” of a cell and force it make new virions, or individual virus particles. The virus or its genetic material enter the cell in order to do this. The new virions break out of the cell, usually destroying it in the process. Each virion can then infect a new cell.

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Real coronavirus particles as seen under an electron microscope (Photo by the CDC, public domain license)

The research team is focusing on the ACE2 (Angiotensin-converting enzyme 2) surface protein on our cells and on a chemical that resembles it. The protein is a receptor, or a protein that attaches to another molecule.

The ACE2 receptor helps to protect our lungs from damage. It’s predominantly present on alveolar epithelial type II cells in the lungs. These cells produce a surfactant that reduces surface tension in the alveoli, or the tiny air sacs in the lungs The surfactant prevents the alveoli from collapsing; This might explain why lung problems develop when the receptor is out of action. The receptor is found in other parts of the body as well as in the lungs.

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An illustration of the alveoli or air sacs (Patrick J. Lynch, via Wikimedia Commons, CC BY-SA 2.5 license)

The coronavirus that causes the COVID-19 disease is officially named the SARS-CoV-2 virus. One of the spike proteins of the SARS-CoV-2 virus attaches to the ACE2 receptor. Once the virus is attached, it’s able to enter the cell and trigger the production of new virions. Multiple researchers are investigating methods that might inhibit the attachment. If the virus doesn’t attach, it won’t be able to infect cells.

The UBC and Karolinska Institute scientists are investigating a drug called APN01, which was created by a company called Apeiron Biologics. The chemical name of the drug is human recombinant soluble angiotensin-converting enzyme 2, or hrsACE2. It’s a genetically-modified version of the ACE2 protein.

The scientists have discovered that in cell cultures and organoids, the modified protein reduces the viral load in cells, apparently by inhibiting the entry of the virus. The researchers suspect that some of the virions bind to the altered protein instead of the one on the cell membrane. In essence, the virus is being tricked. The observation doesn’t mean that the altered protein will work the same way inside our body, but it might.

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Depiction of a coronavirus (Photo by CDC/ Alissa Eckert, MS; Dan Higgins, MAM, public domain license)

A cell culture is a group of cells maintained in lab equipment. Results in cultures can be useful, but the situation inside a living body with all of its structures, processes, and interactions is very different from that in a lab container. The fact that the researchers tested the drug on organoids is a bit more significant, though it’s still no guarantee that it will work inside our body. An organoid is a small and simplified version of an organ. It may be more useful than a cell culture because it contains multiple cell types found in a particular organism, but it’s not a substitute for a living body or even for a complete organ.

The UBC researchers used infected cell cultures as well as organoids that mimicked our kidneys and blood vessels. They discovered that hrsACE2 inhibited the viral load by a factor of 1000 to 5000 in cell cultures. It also “significantly” reduced infection in the organelles.

The researchers admit that there are limitations in their study. They examined the effects of hrsACE2 on cells and organelles that were in the early stages of infection. The result may not be the same in the later stages. Another problem is that the researchers didn’t study the effect of the chemical in lung organoids. The lungs are the major target of the virus. In addition, results inside the human body may be different from those in cells and organelles.

We need to know whether the drug works in patients infected by the coronavirus. We also need to know how significant the inhibition of the virus is. If the drug has no or only a weak inhibitory effect inside the body, it may not be useful. It it inhibits a significant number of virions inside the body,  it may be helpful to some extent and might even be very helpful.

The scientists need to investigate doses, effects, and safety. The drug form of the chemical is not new and is already used medically for other disorders, which should be very helpful in determining safe doses. It’s always good to hear that a known and previously tested drug is being considered for a new disease because it can reduce the time interval before the medicine is available to the public. The maker of APN01 is currently carrying out a clinical trial exploring the effect of the drug on COVID-19. I’m looking forward to hearing about the results.

Even if it’s discovered that the drug is not particularly helpful for the COVID-19 infection in patients, by learning more about the biology of the virus, scientists may have laid the groundwork for new and more applicable research.

References

  • Trial drug effects in engineered human tissue: a press release from the ScienceDaily news service
  • More information about the chemical from the EurekAlert news service
  • A peer-reviewed version of the research article accepted by Cell Press but not yet published in its final form