Behind The Scenes of COVID-19: A study on how novel coronavirus (SARS-CoV-2) works
SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus -2) or as many of you know it the novel coronavirus needs no introduction today. We see a lot of “potential” drugs and vaccines which are administered or under development in different parts of the world, but in reality, we have no real cure. One may wonder, what is taking so long? Why are we not able to find the cure for coronavirus despite having a highly sophisticated and advanced healthcare system? We do know that WHO has launched a global mega trial of 4 most promising drugs for coronavirus treatment, but how were these drugs selected in the first place?
Taking a look into the viruses’ characteristics, its growth and replication will help us answer these!
I would like to answer these questions in three parts. In this part let’s explore how the virus enters the cell. We will explore how it replicates and the logic behind drugs used currently in the subsequent parts.
The common entry points of coronavirus into the human body are through nose, mouth, and eyes. On entering the human body, the coronavirus mediated by ACE2 (Angiotensin Converting Enzyme 2) and TMPRSS2 protease enters the human cell.
A deeper look into how ACE2 and TMPRSS2 helps the virus gain entry
This enzyme’s primary function is to lower blood pressure by catalyzing the conversion of blood vessel constricting proteins (Vasoconstrictor) to blood vessel widening proteins (Vasodilator). Now that you know the functions, some of the organs where its presence should be easy to guess! That said, this enzyme is found on most organs such as lungs, heart, kidney, small intestine, and arterial smooth muscle cells.
How does the SARS-CoV-2 attach to the host receptor ACE 2?
Let’s just start off with the fact that this is not the first virus to enter cells through the ACE2 receptor, its cousin the SARS-CoV virus that caused an outbreak in 2002 also enters through this receptor. The receptor-binding domain (RBD) of these SARS viruses contains a core structure and a receptor binding structure that binds to the outer surface of the claw-like structure of ACE2. Two virus binding hotspots have been identified in ACE 2 which has caused a number of naturally selected mutations in the receptor-binding structure of the virus that helps it become more favorable to bind to ACE2.
SARS -CoV -2 vs SARS -CoV (2002)
There are 14 ACE2 binding residues in the RBD, but here I am going to focus on one of the most important mutations that played an important role in enhancing the cross-species transmission (from civets to humans) of SARS-CoV-2; Residue 493 which is a glutamine residue. One of the viral hotspots in the ACE2 receptor consists of a junction linking Lys31 and Glu35 (Viral hot spot 31) in a hydrophobic environment. This glutamine residue is compatible with the viral hotspot, unlike its earlier cousin SARS-CoV-RBD that occurred in civets where the corresponding residue to 493 was a lysine which couldn’t bind favorably with our hotspot due to steric hindrance and charge repulsion. It is interesting to note the corresponding mutation turned the lysine residue to asparagine residue that helped the cross-species transformation of SARS-CoV(2002)
Other mutations in the RBD domain that help the SARS-CoV-2 bind better to humans than its cousins SARS-CoV (2002) and SARS-CoV (2003) are residues 485, 486, and 494 which are Leucine, Phenylalanine and serine respectively. These are found to have a higher affinity towards the viral hotspots than the corresponding residues in SARS-CoV(2002) that makes the transmission of SARS-CoV-2 from one human to other more favorable and easy.
Role of Cathepsin L and TMPRSS2
The SARS-CoV hijacks many cellular protein cleaving systems to ensure the adequate processing of its S protein. Let’s explore the function of Cathepsin — L and TMPRSS2 which are widely discussed enzymes in this context.
Cleavage of spike protein can be facilitated by cathepsin L, a pH-dependent host cell protease, after the uptake of the virus by the cell through endocytosis ( A fancy way of calling a transport mechanism where substance from the surface of the cell is delivered inside the cell).
Of late, whenever we come across ACE2, we also come across something called TMPRSS2 which stands for Transmembrane Protease Serine type 2 which we safely ignore for the best, but this enzyme plays a vital role in helping the virus by cleaving the spike (S) proteins either at S1 (responsible for receptor binding)/S2 (responsible for membrane fusion)sites, activating the spike proteins to undergo extensive refolding to form a coiled-coil structure that results in virus-cell membrane fusion and thus facilitating the entry of the virus into the cell.
In simple words, the ACE2 helps the virus come to the right address and knock on the door, it is these enzymes that open the door. So not surprisingly, research surrounding the inhibitors of these enzymes is going on worldwide.
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