Sriram, K., Insel, E., & Loomba, R. (2020). What is the ACE2 receptor, how is it connected to coronavirus and why might it be key to treating COVID-19? The experts explain. The Conversation.


University of Michigan - Ann Arbor

- 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

Because ACE and ACE2 are structurally similar, it was thought that existing ACE inhibitor (ACE-I) drugs could be used as a COVID-19 treatment by inhibiting ACE2 activity.  However, because the enzymatic binding sites of ACE and ACE2 are different, ACE-Is do not affect ACE2 activity.  Additionally, COVID-19 patients who took ACE-I drugs were more likely to experience more severe symptoms and had a higher mortality rate than those that didn't take them.  It is thought that ACE inhibition in the RAS may exacerbate the vulnerability of patients with hypertension, diabetes mellitus, or cardiovascular disease to SARS-CoV-2 infection or COVID-19 symptoms.

Using ACE Inhibitors (ACE-Is) to Treat or Prevent COVID-19

ACE2 inhibitors have been shown to have antiviral abilities against other CoVs, but their efficacy has yet to be tested for SARS-CoV-2.  Different ACE2 inhibitors have different functions, with some:

- targeting the ACE2 binding region so that SARS-CoV-2 S protein cannot bind there
- creating recombinant human ACE2 (rhACE2) that "tricks" the virus into binding to the recombinant ACE2 instead of somatic ACE2
- inhibiting the function of TMPRSS2, which would reduce the virus's ability to efficiently enter host cells

Targeting human proteases would be controversial, as there could be many adverse side effects.  Recently, the main SARS-CoV-2 protease structure was determined.  It is thought that an inhibitor to this viral protease could be created, and this could be a promising drug candidate.

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