In December 2019, there began to be an emergence of an invading pneumonia-causing microbe infecting people in the city of Wuhan, China. A novel coronavirus was found to be the cause of this disease and was prominently named 2019 novel coronavirus (2019-nCoV). The disease this virus caused was named COVID-19. Around March of 2020 the situation of the spread of the virus had reached an out-of-control level and on March 11 the World Health Organization (WHO) declared COVID-19 a worldwide pandemic. Formally known as the SARS-CoV-2 along with SARS-CoV (SARS) are viruses that are part of the genus of betacoronavirus of the genus Coronaviridae. The betacoronavirus group can further be divided into four lineages. The SARS type viruses are betacoronavirus lineage β viruses that are known for infecting various mammals.
The coronavirus has four basic components that all play their own part in the virus reproduction. The four main structural proteins including spike (S) glycoprotein, small envelope (E) glycoprotein, membrane (M) glycoprotein, and nucleocapsid (N) protein, and also several accessory proteins. In order to enter the cell the virus must latch onto the host cell’s receptor with the virus’s own glycoprotein spike and then merge its envelope with the host cell to deliver the RNA. The S glycoprotein is composed of two subunits. The S1 domain in its entirety is actually made up of a clove-shaped trimer with three S1 heads. The S1 head is then connected to the envelope of the virus with a trimeric S2 stalk. S1 subunit is responsible for facilitating viral attachment to the host cell and the S2 subunit initiates the merging of the host and virus envelope membranes so the RNA can enter the host cell. Although this structure is common across all coronaviruses, amino acid differentiation in the S glycoprotein limits viruses to particular glycoproteins and organic molecules on the membrane of the host cell to use as receptors.
Reconstruction of the genome of the virus led scientists to believe that SARS-CoV-2 targets the angiotensin producing enzyme 2 (ACM2). The receptor-binding domain (RBD) is the part of the spike that mediates the interaction with the host-cell receptor. For SARS-CoV-2, the RBD is the S1 domain of the spike which contains two subdomains, a N-terminal domain (NTD) and a C-terminal domain (CTD). Both are able to function as RBDs. After binding the receptor, a nearby host protease cleaves the spike of the RBD, which releases the spike fusion peptide, facilitating the virus' envelope merging to the cell membrane of the host cell. After fusion occurs, the type II transmembrane serine protease (TMPRSS2) that is present on the surface of the host cell will give the all clear which leads to conformational changes in the virus that allows the virus’ genetic material to enter the cells.
From here the genomic RNA acts as mRNA for translation to produce two proteins: replicase polyprotein 1a (pp1a) and 1b (pp1b). Then a special type of transformation occurs called Autoproteolytic cleavage. This happening to these polyproteins produces a number of non-structural proteins such as RNA-dependent RNA polymerase, RNA helicase and non-structural proteins 3, 4 and 6. The structural proteins are important because they are responsible for supporting the coronavirus replication transcription complex through calling on the work of intracellular endoplasmic reticulum membranes to form double membrane vesicles. From here RNA dependent polymerase and RNA helicase move towards the double membrane vesicles and lead the charge on the production of subgenomic RNA strands. This step occurring is essential to the lifecycle of SARS-CoV-2 because these RNA strands are instructions from which the structural proteins and accessory proteins are produced in the next stage of translation. Without these proteins, the viral RNA is stranded high and dry after it comes out of replication in the nuclei with no way to travel out of the original host cell and infect another. If these proteins are transcribed then the S, M and E (abbreviated parts of virus - see first part of Life Cycle of SARS-CoV-2) parts of the virus are modified by the endoplasmic reticulum and sent further on to the Endoplasmic reticulum-Golgi intermediate compartment (ENGIC). The N proteins on the other hand, once transcribed are transported to meet the viral genome which has been replicated by RNA polymerase and such elsewhere. Together these form the nucleocapsid. This is sent on to the ENGIC to meet the rest of the virus components for assembly. Mature virions are then exposed from the cell from smooth-walled vesicles via cytokinesis.
Lifecycle of the SARS-CoV-2 virus from entering the host cell to new virions emerging from the cell, while the cell’s machinery remains hijacked.
As mentioned earlier the last thing that has to happen before the virus gain entry to the host cell is that the type II transmembrane serine protease (TMPRSS2) receptor has to give the final all clear to let in a molecule that binds to the ACE2 molecule. The virus can mimic normal biological molecules that bind onto the receptor, but it still has to fool this protease. The success of this happening determines if the virus is able to successfully reproduce so it is critical to target the virus in this stage of its life cycle. Camostat mesilate is a serine protease inhibitor drug that was developed and used to treat other illnesses such as chronic pancreatitis or postoperative reflux esophagitis. Serine protease molecules exist throughout the body so with this drug having multiple uses, quite a few possible side effects could have occurred, but only in extreme cases did anything serious occur. Clinical trials for other illnesses have already been performed and in a 1994 study the dosage amount was perfected. People did not develop any side effects with 600mg doses everyday for an 8 week period. An extreme model was also performed with mice and a lethal injection of SARS-CoV. With Camostat mesilate the survival rate was 60% and that was for a very extreme case. In terms of use in humans against coronaviruses, results are predicted to be promising as in other species the results were good. One or two clinical trials are already in motion and more are currently being planned, but the standing of the effectiveness of this drug is still very much at an undefined point. There is no guarantee that this drug will work. The wrong combination of biological molecules in a given situation can have drastic consequences that were not known before. There is still a lot of unknown territory so scientists and pharmaceutical companies should tread lightly in this area. Another promising solution to the SARS-CoV-2 virus is to target the other molecule involved in the virus’ entry to the host cell: ACE2. The only drug that seems to effectively target this receptor and disrupt the interaction between it and the virus is the common flavone glycoside Hesperidin. This molecule is found in many citrus fruits and has been used as a medicine for a long time. Of the 78 anti-viral drugs that were suggested to work against the human ACE2 receptor and were screened using homology modeling, Hesperidin was the only one that could work. As with the previous drug, using Hesperidin as a treatment option is promising as research into things like the right dosage size and its side effects has already been done. With knowledge such as this, it is very likely that safe administration of Hesperidin as a medicine is quite close. Besides being able to stop SARS-CoV-2 from entering human cells, Hesperidin has anti-inflammatory benefits that can help calm the immune system when it reacts out of control in response to the presence of SARS-CoV-2. Anti-inflammatory activity of hesperidin was mainly attributed to its antioxidant defense mechanism and suppression of pro-inflammatory cytokine production. As much of this possible treatment seems all good, the situation should still be looked at with some skepticism. As with the Camostat mesilate drug, not a huge amount is known about how these treatments will interact with the coronavirus inside the human body. Rushing ahead with these things can lead to mistakes that are easily avoidable so it is important to move through processes like clinical trials as fast as possible while still being cautious.