SARS-CoV-2 S protein has two relevant subunits involved in the pathogenesis of COVID-19: S1 and S2.  S1 has a high binding affinity with the receptor binding domain (RBD) of ACE2.  S2 contains amino acid sequences that are required for the virus to enter host cells.  

Michigan State University

SARS-CoV-2 relies on its spike (S) protein to bind to cellular receptors to enter host cells. SARS-S, the SARS spike protein, uses ACE2 as an entry receptor into cells. Then the virus utilizes the serine protease TMPRSS2 found within the cell to enhance entry and prime future S proteins. SARS‐CoV‐2 is thought to be more transmissible than others CoVs because its S proteins have a greater affinity for ACE2.

ACE2 as a Receptor for SARS-CoV-2

Partridge, L. J., Urwin, L., Nicklin, M. J., James, D. C., Green, L. R., & Monk, P. N. (2020). ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin. bioRxiv.
https://www.biorxiv.org/content/10.1101/2020.05.21.107870v2
doi: 10.1101/2020.05.21.107870

ACE2-independent interaction of SARS-CoV-2 spike protein to human epithelial cells can be inhibited by unfractionated heparin

- Inhibition of the binding between the spike protein present on the surface of the virus and the ACE-2 receptor present in the membrane of the host cell. This interaction mediates the entry of the virus in the cell. 
- Because ACE 2 plays a central role in the pathogenesis of COVID-19, it is thought that it could be an efficient drug target that could either treat or prevent infection. 

ACE2 normal role:
-Critical to regulate processes such as pressure, wound healing, and inflammation. 


-It helps modulate ANGII, a protein that increases blood pressure and inflammation, increasing damage to blood vessel lining and tissue. 

COVID-19:
-In response to COVID-19, ANGII has increased inflammation and the death of alveoli cells which are critical for bringing oxygen into the body...ACE2 prevents this.

-When COVID-19 virus binds to ACE2, it inhibits its action, thus increasing the effects of ANGII
 

ACE 2 Receptor as a Pharmacological Target for Treating or Preventing COVID-19

- HCoV‐NL63

- SARS‐CoV

The receptor binding domain (RBD) of the S protein of these CoVs differ from each other, so it is thought that they utilize different mechanisms to enter host cells.  However, it has been observed that the S protein of SARS-CoV-2 is much more similar to that of SARS-CoV than HCoV‐NL63.  

Other CoVs that Utilize the Human ACE2 Receptor for Entry

The receptor binding domain (RBD) is the part the viral S protein that interacts with human ACE2.  It can exist in two conformations: open (B) or closed (A).  Molecular docking assays have shown that SARS-CoV-2 S protein can interact with the  human ACE2 in both of its conformations (D - open; C - closed).  However, the open conformation interacts protease domain (PD) at a more favorable binding energy than the closed domain which interacts with a different region of ACE2.  This confirms the importance of the open conformation of S protein in SARS-CoV-2. infection. 

SARS-CoV-2 S Protein Conformation and ACE2 Receptor Interaction

ACE2 Interaction with SARS-CoV-2 S Protein by Subunit

A549 are a cell line that do not express ACE2 receptors.  Partridge et al. observed that SARS-CoV-2 S protein interact with these cells even though they do not express ACE2.  Further studies were conducted using two types of 293T cells: cells that express low amounts of ACE2 and cells that over-express ACE2.  S protein interacted with both cell types, but the binding affinity for those expressing low amounts of ACE2 was nearly undetectable.  This suggests that the S protein, specifically the S1 and S2 subunits, may initially interact with host cells via  a different receptor.  However, binding affinity studies suggest that the viral receptor binding domain (RBD) requires higher expression levels of ACE2 to interact with cells.

SARS-CoV-2 S Protein May Interact with Human Cells Independently of ACE2

Five potential binding sites between HCQ/CQ and ACE2 were identified using computerized molecular docking assays.  Reported values are calculated Glide Standard Precision (SP) Glide Extra Precision (XP) measurements which quantify protein/ligand interactions.  These findings support the observation that HCQ is a more effective anti-SARS-CoV-2 drug than CQ in vitro because of HCQ's stronger interaction with the ACE2 allosteric site, which is involved with regulation of the receptor.

ACE2 as a Target for Hydroxychloroquine/Chloroquine in COVID-19 Treatment

Allelic variants in the ACE2 gene has been observed in different ethinic populations, as well as in case-control studies within ethnic groups. However, these are present in relatively low frequencies. Functional studies are encouraged to characterize the relationship between ACE2 variants and COVID-19 severity, but no causal relationship can be made to date.

ACE2 variants and COVID-19

ADAM17 has been demonstrated to upregulate ACE2 expression in cells via a process known as shedding, where it cleaves the extracellular portion of the receptor off of the cell.  Increased ACE2 receptors increases the number of SARS-CoV-2 viral receptors on the cellular surface, and this may exacerbate the infection or COVID-19 symptoms.  

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