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The COVID targets- RNA virus. SARS COV2 shares nearly 80% genetic analogy with previous SARS COV particularly for spike glycoprotein. There are two subunits of spike glycoprotein but this is how it attaches to receptors on human cells
The spike glycoprotein attaches to ACE2 receptors on human cells. These receptors found in respiratory tract and lungs, intestines in epithelium and organs like liver and kidney in endothelium. Epithelial ACE2 receptors are initial targets, that explains resp and GI symptoms.
The easiest target for vaccine production is spike glycoprotein. If you develop antibodies against glycoprotein the virus is basically not effective. The problem with this 1) High risk of mutation with season (like influenza) 2) Question on efficacy (like its not 100% effective)
TMPRSS2-Transmembrane serine protease 2 is present on host cell and it primes the spike glycoproteins facilitating entry of virus. Non specific serine protease inhibitors are not effective in clinical trials. Can we use TMPRSS2 specific inhibitor like camostat mesylate?
Camostat is used in Japan to treat pancreatic inflammation and is inhibitor of TMPRSS2. In article published in cell, camostat and nafamostat worked invitro to prevent entry of virus in cell.
(DOI: https://doi.org/10.1016/j.cell.2020.02.052)https://doi.org/10.1016/j... href=" https://www.contagionlive.com/news/could-a-japanese-encephalitis-drug-prevent-covid19">https://www.contagionlive.com/news/coul...
(DOI: https://doi.org/10.1016/j.cell.2020.02.052)
ACE2-I believe the answer for cure may lie in blocking ACE2 receptor( no drug found yet but you can target the site with antibodies) or competetive blocking by delivering extra soluble ACE2. To understand how this is possible, let us understand renin angiotensin axis.
ACE2 receptors are critical for alternative RAAS pathway and protecting the lungs from injury and inflammation. The virus destroys ACE2 cells leading to promotion of classical RAAS pathway with more lung inflammation and fibrosis
ACE inhibitors like Lisinopril can block ACE inflammatory pathway but the risk is that upregulate ACE2 in turn because of increased angiotensin 1 levels and facilitate more viral entry and replication through ACE2. This may be counterproductive if virus overpopulates ACE2 cells.
We do not know if direct renin inhibitors may be better than ACE inhibitors to decrease angiotensin 1 level, downregulate and protect ACE2 receptors and decrease classical inflammation mediated RAAS pathway. No clinical trials on direct renin inhibitors yet.
Once the virus enters inside the cell than it travels to endosomes and lysosomes to nuclear structure where it uses cell nuclear replicates and forms copies through processes of transcription and translation
Hydroxychloroquine (invitro) modifies ACE2 receptor by glycosylation preventing viral entry as well as affect viral endosome-lysosome move by change in pH. HCQ has 10-12 times concentration in lungs compared to plasma and high Vd. May help in early stage
https://www.nature.com/articles/s41421-020-0156-0.pdf">https://www.nature.com/articles/...
https://www.nature.com/articles/s41421-020-0156-0.pdf">https://www.nature.com/articles/...
The last target is inhibiting the viral replication inside the cell. They do not inhibit cell entry.. Drugs like favipiravir and remdesivir will have this mechanism of action. Favipiravir is unique for activity against viral RNA polymerase. May help in late stage
