COVID-19 has become increasingly prevalent with each passing day. The malicious virus has taken hundreds of thousands of lives, caused millions of job losses, and most importantly, has forced billions of people into quarantine. It is amusing how this minuscule molecule indiscernible by the naked eye has caused such drastic large-scale effects. In order to fully comprehend the dreadful effects of coronavirus, it must be scrutinized at a molecular level.
A deeper dive into the protein structure of the coronavirus will show why it is so viral. Proteins consist of long chains of forty or more amino acids linked by peptide bonds, while peptides are chains of fewer than forty amino acids. Similarly, a protease is a type of protein that hydrolyzes proteins in the body in order to break peptide bonds and decompose them into their simplest form: the amino acid. Amino acids consist of an amino group (NH2), a carboxyl group (COOH), and a unique R group that identifies the amino acid. Mpro, the protease responsible for replication, is composed of chains of complex amino acids that form a globular protein: proteins coiled into a spring–like structure.
Figure 1: going from left to right, the globular protein of Mpro, the complex of Mpro and its inhibitor, and the binding between Mpro and an inhibitor
How does the virus enter the body?
The spike proteins (glycoprotein) of the single-strand RNA virus strongly bind to Angiotensin-converting enzyme 2 (ACE2) via an electrostatic interaction to infiltrate the body. This electrostatic interaction is a non-covalent force that involves a positively charged coronavirus molecule and the negatively charged ACE2. The glycoprotein of the spike is a protein with over 1000 amino acids with a carbohydrate group attached to it, which consists of hydroxyl groups. The glycoprotein consists of two subunits, S1, the globular protein used for receptor binding, and S2, the fibrous protein used for transcription of the virus by way of membrane fusion. ACE2, a globular enzyme that contains a peptidase domain for substrate binding, is a key receptor that is found in the lungs. In the interaction shown in figure 2, the amino acids of the S1 subunit non-covalently bonds to the N-terminal of the peptidase domain of ACE2. More specifically, it uses the histidine and asparagine amino acids of the peptidase domain to bind to the amino acids of spike proteins.
In addition, the spike protein attacks furin, an enzyme lined along many organs in the body such as the lungs, intestine, and liver. As a result, symptoms of coronavirus include lung failure and liver problems. Once it is in the body, it replicates itself by using its active sites enclosed in the protease (Mpro). As shown in figure 1, the active sites are the holes in the molecule that the substrate molecules fit perfectly into. The active sites bind to substrates to invade new cells. Since the virus mainly attacks the lungs, natural actions such as breathing spread the virus through air droplets. The air droplets contain particles of the virus, and when it encounters an organism, it then attacks that host cell and the process is repeated.
Figure 2: The binding of the glycoprotein to ACE2
Since it is a globular protein, Mpro can easily be transported throughout the aqueous environment of the blood because of its hydrophilic structure. Once the coronavirus enters the cell, the Mpro protease rapidly hydrolyzes the amides of the peptide in coronavirus. As a result, the peptide bonds break and split into individual amino acids, which can aid in producing more virus cells. The peptide gets cleaved in between the sigma C-N bond, as shown in figure 3. As a result, the process of amide hydrolysis occurs, which aids RNA replication. As shown in figure 4, the amide hydrolysis is performed with the help of a cysteine, which acts as a nucleophile in the reaction. After all, the virus replicates other host cells, which explains the contagiousness of this virus.
Figure 3: chemical structure of the peptide
Figure 4: amide hydrolysis of Mpro
The Inner Workings of the Vaccine
With a rapid increase in cases of COVID-19, demand from the general public for a vaccine or treatment has escalated. A molecule that could mimic the actions of the peptide would be able to stop the amide hydrolysis of Mpro. An inhibitor would require an electrophilic warhead that could accept electrons just as the peptide does. At last, the vaccine or treatment boils down to something that could block the active site of Mpro from binding to the substrate. Researchers at massive medical companies such as Pfizer and Moderna have done research on just that to produce a vaccine. After months of apprehension, toil, and dread, a molecule that could perfectly bind with the active site, like a key and lock, has been found. As a competitive inhibitor, it would block the substrate from binding to its active site and thus increase the substrate concentration needed to bind to that enzyme. As a result, it would reduce the spread of the virus throughout the body and prohibit replication.
Figure 5: Lock and key mechanism of the active site of Mpro
The sophisticated chemical structure of Mpro and complicated biological processes behind COVID-19 explain why it is so lethal. A thorough understanding of these details will help scientists create prophylactic drugs and coronavirus treatments. As vaccines get perfected and treatments start to develop, the world will begin to return to normalcy.
Works Cited
Assay Genie. 2020. How Furin And ACE2 Interact With The Spike On SARS-Cov-2. [online] Available at: <https://www.assaygenie.com/how-furin-and-ace2-interact-with-the-spike-on-sarscov2> [Accessed 6 July 2020].
Cyranoski, D., 2020. Profile Of A Killer: The Complex Biology Powering The Coronavirus Pandemic. [online] Nature.com. Available at: <https://www.nature.com/articles/d41586-020-01315-7> [Accessed 6 July 2020].
Figure 1, Jin, Z., Du, X. and Xu, Y., 2020. Structure Of Mpro From SARS-Cov-2 And Discovery Of Its Inhibitors. pp.1-3.
Figure 2, What we do and don't know about the novel coronavirus. https://cen.acs.org/biological-chemistry/infectious-disease/novel-coronavirus-hits-China/98/web/2020/01 (accessed Jul 27, 2020).
Figure 2, Researchers in China report structure of the novel coronavirus bound to its human target. https://cen.acs.org/biological-chemistry/biochemistry/Researchers-in-China-report-structure-of-the-novel-coronavirus-bound-to-its-human-target/98/web/2020/03