Spironolactone inhibits ACE2 expression on the epithelium of lung tissue, and could potentially replace ACE inhibitors. COVID-19 patients could face withdrawal from ACE inhibitors, which could be prevented by using spironolactone. 


Michigan State University

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.

Using ACE2 Inhibitors to Treat or Prevent COVID-19

Cadegiani, F. A. (2020). Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?. American Journal of Physiology-Endocrinology and Metabolism, 318(5), E587-E588.

Can spironolactone be used to prevent COVID-19-induced acute respiratory distress syndrome in patients with hypertension?

- Elevated plasmin levels are found in COVID-19 patients
- Plasmin allows the SARS-CoV-2 virus to bind with ACE2 receptors by cleaving the S protein on the virus
- Plasmin breaks down fibrin, increasing the levels of D-dimer and decreasing platelet count; this could possibly prevent inflammation in COVID-19 patients, but it could result in hemorrhaging
- Plasminogen is expressed in both endothelial and epithelial cells
- Severe and deceased COVID-19 patients had very low platelet counts
- However, plasmin causes hypertension and dehydration in the lungs due to an increase in sodium ion uptake


Plasmin and COVID-19

Spironolactone as a potential replacement for ACEI

- the novel compounds under development is human recombinant soluble ACE2 (hrsACE2 [APN01; Apeiron Biologics, Vienna, Austria])
- 2 benefits: 
1. binding the viral spike protein and thereby neutralising SARS-CoV-2.
2. minimising injury to multiple organs, including the lungs, kidneys, and heart, because of unabated renin–angiotensin system hyperactivation and increased angiotensin II concentrations
- hrsACE2 can reduce SARS-CoV-2 load by a factor of 1000–5000 in in-vitro cell-culture experiments
- hrsACE2 has been tested in 89 patients. After the first injection of hrsACE2 we observed a marked reduction of angiotensin II. Concurrent with reduced angiotensin II concentrations we detected a marked reduction in the inflammatory cytokine interleukin (IL)-6 and chemokine IL-8, both of which play an important role in lung injury and cytokine storm.
- hrsACE2 can reduce the cytokine storm which is the killer for COVID-19 patients


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