Can Soluble ACE2 Provide Total Protection from COVID-19?

How do coronaviruses infect your body? SARS-CoV-2, like SARS-CoV and several other coronaviruses, uses angiotensin converting enzyme 2 (ACE2) as a means to enter target cells. ACE2 is a human enzyme involved in the regulation of blood pressure. It acts as a counterbalance to the angiotensin converting enzyme (ACE) that converts angiotensin I to angiotensin II, by in turn converting angiotensin II to angiotensin (1-7). Angiotensin II is a vasoconstricting hormone, meaning that it increases the blood pressure by causing the blood vessels to become narrower, whereas angiotensin (1-7) is a vasodilator, with the opposite effect of widening the blood vessels (Kuba et al.).

Hence, ACE2 is a crucial actor in keeping our blood pressure down; in fact, one of the reasons behind the association of cardiovascular disease and COVID-19 could be that “the entry of SARS-CoV-2 into the cells…down-regulated ACE2 receptors,” leading to angiotensin II going through alternative reaction pathways, detrimentally affecting one’s cardiovascular health (Verdecchia et al.).

According to Medina-Enríquez and her colleagues’ research, there are two forms of ACE2:

1. The channel form that acts as a transmembrane protein (mACE2)

2. The soluble form circulating in small quantities in the blood (sACE2)

mACE2, the first form, docks with the spike protein (also known as the S-protein) on the SARS-CoV-2 surface leading to subsequent virus internalization via endocytosis, in which the viral particle enters the cell in an envelope made of a small part of the cell membrane. Interestingly, SARS-CoV-2’s S-protein is better at binding to mACE2 than SARS-CoV’s S-protein, which could be one of the factors explaining the lesser spread of the SARS-CoV pandemic in 2003 in comparison to the current SARS-CoV-2 pandemic (Wang et al.; Medina-Enríquez et al.).

As for sACE2, it has been suggested that it can function as a “decoy ligand to sequester SARS-CoV-2 away from the membrane receptor ACE2,” thus reducing the harm done by the virus (Medina-Enríquez et al.). Following this line, a new potential treatment for COVID-19 has been developed: inserting human soluble ACE2 that intercepts the SARS-Cov-2 S-spike before it can bind to cells (Hassler et al.).

Luise Hassler and her colleagues synthesized short human ACE2 variants, fused with a small albumin-binding domain to extend the lifetime of the drug in the body. Albumin is a molecule that helps hormones, enzymes, and other molecules stay in the bloodstream. Furthermore, the authors dimerized ACE2 for enhanced binding with the S-Trimers; the resulting dimer, which is a molecular structure with two identical units, can simultaneously bind to two S-proteins, thus “covering more ground.”

Intranasal administration of three doses of the resulting ACE2 1-618-DDC-ABD protein—the name coined by Hassler and his colleagues—almost completely prevented lethal outcome in transgenic mice inoculated with COVID-19 with only 1 out of 10 mice dying on day 14, as opposed to the control group, where all the mice died. Such a drastic difference brings optimism and hope for protecting and fighting against COVID-19.

Treatment with the ACE2 1-618-DDC-ABD protein also resulted in a decreased amount of SARS-CoV-2 particles in the lungs and reduced overall lung damage. Although the Hassler’s study discussed is pre-print, meaning that it has not been peer-reviewed yet, and there exist opposing views on the effect of sACE2 on SARS-CoV-2 infectivity (Yeung et al.), these results do indicate the possibility of using soluble ACE2 as a possible treatment solution to fool SARS-CoV-2 and prevent severe COVID-19 infections in the future!

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Works Cited:

1. Hassler, Luise, et al. “A Novel Soluble ACE2 Protein Totally Protects from Lethal Disease Caused by SARS-CoV-2 Infection Short Title: Novel Soluble ACE2 to Combat SARS-CoV-2.” BioRxiv, 2021, p. 2021.03.12.435191, https://doi.org/10.1101/2021.03.12.435191.

2. Kuba, Keiji, et al. “Multiple Functions of Angiotensin-Converting Enzyme 2 and Its Relevance in Cardiovascular Diseases.” Circulation Journal, vol. 77, no. 2, Circ J, 2013, pp. 301–08, doi:10.1253/circj.CJ-12-1544.

3. Medina-Enríquez, Miriam Marlene, et al. “ACE2: The Molecular Doorway to SARS-CoV-2.” Cell and Bioscience, vol. 10, no. 1, BioMed Central Ltd, 2020, pp. 1–17, doi:10.1186/s13578-020-00519-8.

4. Verdecchia, Paolo, et al. “The Pivotal Link between ACE2 Deficiency and SARS-CoV-2 Infection.” European Journal of Internal Medicine, vol. 76, Elsevier B.V., 1 June 2020, pp. 14–20, doi:10.1016/j.ejim.2020.04.037.

5. Wang, Qihui, et al. “Structural and Functional Basis of SARS-CoV-2 Entry by Using Human ACE2.” Cell, vol. 181, no. 4, Cell Press, May 2020, pp. 894-904.e9, doi:10.1016/j.cell.2020.03.045.

6. Yeung, Man Lung, et al. “Soluble ACE2-Mediated Cell Entry of SARS-CoV-2 via Interaction with Proteins Related to the Renin-Angiotensin System.” Cell, vol. 184, no. 8, Elsevier B.V., Apr. 2021, pp. 2212-2228.e12, doi:10.1016/j.cell.2021.02.053.

Last Fact Checked on May 21st, 2021