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HomeClinical TrialsPre-Clinical ResearchIdentifying the SARS-CoV-2 receptor: implications for disease treatment

Identifying the SARS-CoV-2 receptor: implications for disease treatment

In the first step toward developing effective COVID-19 treatments, scientists successfully identify receptors that allow the virus to enter cells.

Every new confirmed case of COVID-19 adds to the mounting pressure to develop a treatment or vaccine. But how are treatments or vaccines created, and why does it take so long? 

What do we know about COVID-19?

To develop a therapy for a particular disease, we need to understand its basic biology. So what do we know about COVID-19? Well as it turns out quite a bit, COVID-19 is the name for the respiratory illness people get from a virus called SARS-CoV-2 (previously called 2019-nCoV). This virus is part of the Coronaviridae family of viruses, which are enveloped single-stranded RNA viruses that normally cause mild respiratory diseases in humans and animals. In 2002, however, this changed dramatically with the outbreak of severe respiratory syndrome coronavirus (SARS-CoV) in Southern China, which caused serve illness and in some cases death. SARS-CoV and SARS-CoV-2 are members of the same virological family and are both Coronaviruses meaning they are closely related and share some sequence homology. Why does this matter?

Can SARS-CoV help us understand SARS-CoV-2?

The similarities between these two viruses give scientists a place to start. If we know how SARS-CoV works, perhaps SARS-CoV-2 will work in the same way?  For instance, we know how SARS-CoV can gain entry into a cell.  It uses the proteins on its surface, called spike proteins to bind to a receptor on the host cell’s surface. The receptor is called ACE2 (angiotensin-converting enzyme 2). Scientists have also shown that the spike protein needs to be processed by host enzymes to allow fusion with the cellular membrane. Two host proteins are responsible for this – cathepsin L and TMPRSS2 (transmembrane protease serine 2).  It is critically important to identify which proteins give the virus access to the cell because if you can disrupt these interactions you can prevent infection and potentially develop a treatment for the disease.

Scientists investigate SARS-CoV-2 mechanism of viral entry

In a recent study published in Cell, researchers from Germany wanted to know if SARS-CoV and SARS-CoV-2 use a similar mechanism for gaining entry into the host cell. They also wanted to know whether or not this process could be blocked.

The scientists began by engineering a vesicular stomatitis virus (VSV) so that it would have the same spike proteins as SARS-CoV and SARS-CoV-2.   The team wanted to determine if the spike proteins from each virus would allow infection in the same types of cells. They infected well-characterised cell lines from human and animals and found that both proteins facilitated entry into similar cell types. This suggests that the two spike proteins use similar receptors to gain access to a target cell. 

Is ACE2 a receptor for SARS-CoV-2?

The researchers then went on to look at the amino acid sequence of each spike protein and found that the residues used for interaction with the ACE2 receptor were present on both proteins. The scientists then used BHK-21 cells that were not susceptible to infection and genetically engineered them to express human or bat ACE2 proteins. When the cells were expressing the receptor they became susceptible to infection by viruses that had either the spike protein from SARS-CoV or SARS-CoV-2. The team also used authentic SARS-CoV-2 virus to infect these cells and found a similar result. These experiments showed that ACE2 was the receptor protein for SARS-CoV-2. 

Does SARS-CoV-2 use cathepsin L and TMPRSS2 to get into the cell?

The researchers were also interested to know if SARS-CoV-2 required the aid of an enzyme to enter the cell in the same way SARS-CoV needs cathepsin L. The team treated two separate cell lines with ammonium chloride, which blocks cathepsin L activity and found that treatment prevented viral entry into these cells. This suggests that cathepsin L is required for SARS-CoV-2 entry. The researchers then went on to use camostat mesylate, this is an inhibitor of TMPRSS2. They found that inhibition of TMPRSS2 partially prevented viral entry for viruses with SARS-CoV-2 spike protein. The researchers wanted to know the virus used these proteins to gain entry into lung cells.  They found that camostat mesylate treatment prevented SARS-CoV-2 from entering lung cell lines and lung cells taken from patients. These experiments proved that SARS-CoV-2 can use both cathepsin L and TMPRSS2 to gain entry into a cell.

Although the results presented in this article are compelling, there are a few considerations to take into account. In many of the experiments, the researchers did not use SARS-CoV-2 virus but VSV and some of the findings presented will need to be confirmed using SARS-CoV-2. The authors state that using camostat mesylate may be a potential therapeutic as it prevented viral entry and is already approved for clinical use in Japan. Camostat mesylate is however approved for the treatment of chronic pancreatitis, therefore a new clinical trial for its use as a therapy for SARS-CoV-2 would still have to be undertaken to determine dosage and safety in a population of people suffering from a separate medical condition. Additionally, the team showed that SARS-CoV-2 is also capable of using cathepsin L to gain entry into cells and inhibiting TMPRSS2 alone may not be sufficient to prevent viral infection and spread. While the work presented here is a step in the right direction, all the work presented was performed in the lab. Any new potential therapeutic molecule that could be used for COVID-19 treatment would be years away from approval as additional animal studies and clinical trials would need to be conducted before FDA or EMA approval was provided.

So where does that leave us? For now, prevention is better than cure to avoid getting sick stick to the WHO guidelines; wash your hands frequently, cough and sneeze into your elbow, avoid touching your face and maintain social distancing. 

Written by Tarryn Bourhill MSc, PhD Candidate.

References:

1              Dong E, D. H., Gardner L. Wuhan Coronavirus (2019-nCoV) Global Cases <https://gisanddata.maps.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6> (2020).

2              Simmons, G., Zmora, P., Gierer, S., Heurich, A. & Pöhlmann, S. Proteolytic activation of the SARS-coronavirus spike protein: cutting enzymes at the cutting edge of antiviral research. Antiviral research 100, 605-614 (2013).

3              Sahin, A. R. et al. 2019 Novel Coronavirus (COVID-19) Outbreak: A Review of the Current Literature. EJMO 4, 1-7 (2020).

4              Zhang, H., Penninger, J. M., Li, Y., Zhong, N. & Slutsky, A. S. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Medicine, 1-5 (2020).

5              Chhikara, B. S., Rathi, B., Singh, J. & Poonam, F. Coronavirus SARS-CoV-2 disease COVID-19: Infection, prevention and clinical advances of the prospective chemical drug therapeutics. Chemical Biology Letters 7, 63-72 (2020).

6              Hoffmann, M. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell (2020).

7              Organisation, W. H. Coronavirus disease (COVID-19) advice for the public, <https://www.who.int/emergencies/diseases/novel-coronavirus-2019/advice-for-public> (2020).

Image by Cassiopeia_Arts from Pixabay   

Tarryn Bourhill MSc PhD Candidate
Tarryn Bourhill MSc PhD Candidate
Tarryn has a Master’s degree in Molecular Medicine from the University of the Witwatersrand, South Africa. She is currently pursuing a PhD in Molecular Biology and Biochemistry at the University of Calgary. Tarryn specializes in cancer, oncolytic viral therapy and stem cell research. She is passionate about scientific communication and enjoys turning complicated ideas into approachable and engaging conversations. In her spare time, Tarryn is a keen baker and a photography enthusiast.
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