Alpha-lipoic acid (ALA) is a drug that is currently used to treat diabetic polyneuropathy.  It increases insulin signalling sensitivity, functions as an antioxidant, and inhibits NF-kB activity.  Additionally, ALA has been demonstrated to have anti-viral properties.  Its ability to reduce NF-kB activity, increase intracellular glutathione concentrations, chelating metal ions, and restoring antioxidant levels have all been shown to have protective effects against different viruses.  ALA may be specifically useful in treating or preventing COVID-19 because of its ability to prevent ACE2 upregulation by inhibiting ADAM17, increasing intracellular pH by activating sodium/potassium pumps, and increasing the amount of intracellular antioxidants to bolster the host cell's defense mechanism.  

Using Alpha-Lipoic Acid (ALA) to Treat or Prevent 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.  

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

While the mechanism remains unclear, it has been hypothesized that this type I sheddase transmembrane protein is involved in the pathogenesis of COVID-19.  Evidence that suggests that ADAM17 may be involved include:

- its known role in SARS-CoV viral uptake into host cells
- activating TNF‐α through cleave in cases of lung inflammation
- an association between high ADAM17 tissue expression and TNF‐α in an animal model of COPD, a known risk factor of COVID-19
- elevated ADAM17 gene expression in type II diabetic patients with diabetic low‐density lipoprotein (LDL)
- suggested contribution of ADAM17 to inflammation by stimulating IL-8 release
- proposed role in lung fibrosis and COPD through its ability to cleave IL-6R

ADAM17 in the Pathogenesis of COVID-19

Cure, E., & Cure, M. C. (2020). Alpha-lipoic acid may protect patients with diabetes against COVID-19 infection. Medical Hypotheses, 110185.
https://www.sciencedirect.com/science/article/pii/S0306987720310604?casa_token=Q4ATHQoHhWUAAAAA:CBkMfamaSgvWCDxvhZOPzwcnfIWZXdqCdHXlGFWAW5WQkqtqhKmEasZEVJLmDsrexTcJ1yU2mQ
doi: 10.1016/j.mehy.2020.110185

Alpha-lipoic acid may protect patients with diabetes against COVID-19 infection

- 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

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.  

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 Induced ACE2 Upregulation May Contribute to SARS-CoV-2 Infections

- cleavage of ACE2 requires Arg and Lys residues within ACE2 amino acids 652-659
- cleavage of ACE2 by ADAM17 does not promote spike protein entry, unlike TMPRSS2
- competes with TMPRSS2 for ACE2 processing

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