Analyzing COVID pharmacology
The novel corona-virus continues to puzzle researchers
around the world, thereby raising risks to magnanimous scales. However, the
good news is that the human efforts are matching its levels as well. One such research
was performed by Dr. Daniel Jacobson’s group who utilized worlds second fastest supercomputer at Oak
Ridge National Lab in Tennesse and studied around 2.5 billion genetic combinations.
Even with such powerful super-computer, it took more than a week. Their results have
been published in the journal eLife in early July. The research is summarised below using a flowchart for convenience.
Basically, COVID enters through binding to ACE2 receptors present in higher concentrations inside the nose. Upon entering it attacks other places with higher ACE2 concentration, that is, intestines, kidneys, heart etc. Interestingly COVID not only attacks these receptors but it also increases the concentration of these receptors at places where they are present in low or medium concentrations. Therefore, ACE2 receptors play an important role for coronavirus. It is important to note that people with hypertension have higher ACE2 receptors than others, possibly, therefore, making them more susceptible to infection. However, the exact relationship between ACE concentration and severity of infection is yet to be explored.
Moving ahead, by binding to ACE2 receptors coronavirus interferes with an important biological system, renin-angiotensin system, RAS, which controls our blood pressure. The interferences result in bradykinin storm, which is believed to be the reason behind weird and serious symptoms seen in COVID patients. Higher bradykinin levels are said to cause cough, fatigue, lower blood pressure, the textbook symptoms. Bradykinin storm also increases capillary permeability which results in inflammation, breakage of the blood-brain barrier and sore toes. All these have been observed in COVID patients. Breakage of blood-brain causes infection to attack the brain, thereby damaging the brain and neural network. In addition, bradykinin storm also increases hyaluronic secretion. This when combines with leaked fluid form a hydrogel like substance in alveoli. This explains the ineffectiveness of ventilators for serious cases.
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| Proposed pathway (made by author) |
The research, therefore, suggests that the drugs which can help control bradykinin levels and HLA might be able to keep COVID effects in check. Interestingly vitamin-D (present in sunlight) is involved in the RAS system and maybe a natural medicine.
Some strands of literature have also discussed the Ang mechanism. Actually also includes RAS mechanism interference but along a slightly different path. For this, the RAS system needs to be understood slightly more in-depth. The major suggested pathways from such researches have been very summarized using a flowchart below.
The RAS system starts from Angiotensin, which is a liver secreted protein. Renin (coming from kidney) then converts it into Angiotensin-1 (ang-1) by cleaving the first few amino acids of angiotensin. Ang-1 is then converted into Ang-2 by Angiotensin-converting enzyme (ACE-1). Ang-2 peptide hormone increases blood pressure and injures cells, and therefore needs to be in check. Therefore, while ACE1 increases Ang-2, ACE-2 keeps its level balanced by converting Ang-2 into Ang-1-7. ACE2 also converts Ang-1 into Ang-1-9. They have their own set of utilizations which I would not go into. Now importantly, ACE2 is also involved in the degradation of bradykinin, therefore maintaining its level too. For COVID-19, ACE2 is the heaven, as it is here where the virus attaches itself to. By attaching to ACE2 it inhibits its activities and then as discussed in the process above creates disequilibrium in the RAS system and bradykinin levels.
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| Renin-Angiotensin System |
References:
2. Angiotensin and the coronavirus, by Derek lowe,, Science Translational Medicine
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