Targeting ACE2 – Closing COVID-19’s cellular doorway

Targeting ACE2 – Closing COVID-19’s cellular doorway

Since the outbreak of COVID-19, caused by SARS-CoV-2 virus, scientists have been racing to understand this virus, elucidate the mechanism for disease progression and identify treatment options for this novel, pandemic disease. Extensive research has been devoted to identifying viable genes and proteins as targets for therapeutic agents. One particular protein that has drawn considerable

Since the outbreak of COVID-19, caused by SARS-CoV-2 virus, scientists have been racing to understand this virus, elucidate the mechanism for disease progression and identify treatment options for this novel, pandemic disease. Extensive research has been devoted to identifying viable genes and proteins as targets for therapeutic agents. One particular protein that has drawn considerable attention is the human cell’s viral receptor, angiotensin-converting enzyme 2 (ACE2).

 

The basics of ACE2

ACE2 is a membrane protein with an enzymatic domain located on the outer surface of human cells. It was so named because this protein was initially identified as a homolog (or a variant) of angiotensin-converting enzyme (ACE), an enzyme that mediates the formation of the peptide hormone, angiotensin II from angiotensin I. ACE has been studied extensively and is a well-known vasoconstrictor (i.e., it causes muscle contraction in the blood vessel wall and narrowing of the blood vessel lumen). 

ACE2, now known to be a viral receptor, also acts as a vasodilator, which counterbalances ACE and causes blood vessel walls to relax. Both ACE and ACE2 are important players in the renin- angiotensin system (RAS) that regulates blood pressure and blood flow to multiple organs, including the lungs, heart and kidneys. RAS encompasses a complex network of enzymes, peptide hormones and receptors as shown in Figure 1. Angiotensinogen, the angiotensin (Ang) precursor, secreted by the liver, is cleaved by the kidney enzyme renin to produce Angiotensin I (Ang I). Ang I is then converted to Ang II by ACE. Ang II, an eight-amino acid hormonal peptide, binds to type 1 angiotensin receptors (AT1R) on the surface of muscle cells in small blood vessels to cause vasoconstriction. It also promotes sodium reabsorption by the kidneys. Both vasoconstriction and sodium reabsorption lead to an increase in blood pressure. Thus, abnormally high ACE activity leads to increased levels of Ang II, causing hypertension. Conversely, ACE2 catalyzes conversion of the eight-amino acid peptide, Ang II, to a seven-amino acid peptide (Ang 1-7), which appears to have the opposite effect of Ang II via its action on a different receptor, called Mas receptor (MasR). While the precise role of Ang 1-7 in blood pressure regulation has not been fully elucidated, evidence exists that it lowers blood pressure and induces vasodilation. In addition, ACE2 cleaves Ang I to Ang 1-9, and therefore may further counterbalance the effect of ACE by removing its substrate. By causing conversion of Ang II to Ang (1-7) and Ang I to Ang 1-9, ACE2 may play a role in maintaining the balance between vasoconstriction and vasodilation to keep blood pressure in check. 

renin angiotensin system
Figure 1. The renin-angiotensin system (RAS) and the role of ACE, ACE2, Ang II, Ang (1-7), AT1R and MasR in the regulation of blood pressure

The role of ACE2 in SARS-CoV-2 infection

ACE2 can be recognized by the spike protein (S protein) on the surface of SARS-CoV-2 or SARS-CoV virus. ACE2 and S protein bind in a fashion analogous to a lock-and-key interaction, which enables the virus to enter human cells (Figure 2). 

coronavirus protein interaction
Figure 2. Illustration of coronavirus S protein interaction with ACE2 on human cells (Source:     ACS Cent. Sci. 2020, 6, 3, 315-331).

Although SARS-CoV-2 is very similar to SARS-CoV, the virus that caused SARS (Severe Acute Respiratory Syndrome), a few mutations in the receptor binding domain of the S protein have significantly increased the SARS-CoV-2 virus’ binding affinity to ACE2. These differences may underpin the higher transmissibility of COVID-19. There is evidence that ACE2 is expressed in our lungs, digestive systems, hearts, arteries and kidneys. ACE2 expression also increases with age and is higher in patients suffering from cardiovascular diseases, potentially explaining the increased severity of COVID-19 in these subgroups.

While functioning as the docking site for SARS-CoV-2 and mediating virus entry into the host cells, ACE2 may not act alone in this process. Other host enzymes are also involved in facilitating viral entry. Enzymes called proteases are responsible for removing fragments both from ACE2 and S protein to enhance their interaction process. Other enzymes modify the ACE2-S protein complex packed in membrane-bound vesicles to facilitate viral entry into the host cell. Therefore, ACE2 and its interaction with SARS-CoV-2, as well as other proteins involved in this process, are conceivably valid targets for anti-COVID-19 agents.

Upon viral binding, it is speculated that the catalytic domain of ACE2 may be blocked by the virus, resulting in limited access to the substrate, Ang II, causing Ang II accumulation. Additionally, with viral entrance, the surface ACE2 may be internalized to the cells, therefore decreasing ACE2 enzymatic function (Figure 3). As a result of reduced ACE2 activity, circulating Ang II levels may increase, as has been reported in COVID‐19 patients. The Ang II level exhibits a linear positive correlation to viral load and lung injury, indicating a direct link between tissue ACE2 downregulation, with RAS imbalance, and the development of organ damage in COVID-19 patients. More studies, however, are needed to confirm this finding.

inaccessibility ace2
Figure 3. SARS-CoV-2 infection causes inaccessibility of ACE2 to its substrates and internalization of ACE2 in the cells, resulting in increased blood pressure and vasoconstriction.

The potential of ACE2 as a target for COVID-19 therapies

Due to the crucial role ACE2 plays in host cell invasion by SARS-CoV-2, efforts are underway to develop drugs that can block its function in this capacity. To date, no small-molecule drug has been approved via drug repurposing for this application. However, a biologic drug has been developed recently that may achieve this goal. This clinical-grade drug, human recombinant soluble ACE2 (hrsACE2), was originally designed for acute respiratory distress syndrome (ARDS). The hrsACE2 does not have the membrane-attachment segment, and thus, does not attach to human cells. However, it is capable of binding SARS-CoV-2 virus as a decoy receptor. By competitively binding to this coronavirus, it prevents viral binding to the natural, membrane-bound ACE2, and thus blocks virus entry into host cells (Figure 4). Studies in cultured cells and various organoids have showed that hrsACE2 indeed inhibited the virus from infecting the host cells. It also appeared to be well tolerated and elicited a rapid decrease in serum Ang II levels in ARDS patients in a 2017 clinical trial. It is hopeful that hrsACE2 may be the first drug that targets ACE2 and will open the door for targeted therapies in the fight against COVID-19.

ACE2 blocking SARS Cov-2 binding
Figure 4. Illustration of how hrsACE2 may block SARS-CoV-2 binding to ACE2, and thus, viral entry into the host cells.

 

Soruce: https://support-cas-org.ezproxy.uindy.edu/blog/ace2-covid-19-target

admin
ADMINISTRATOR
PROFILE

Posts Carousel

Leave a Comment

Your email address will not be published. Required fields are marked with *

Latest Posts

Top Authors

Most Commented

Featured Videos

php shell hacklink php shell seo instagram takipçi satın al php shell plak alanlar iqos okey oyna