Fighting Against COVID-19: From Molecular Biology to Clinical Treatment

Humanity is currently fighting against a major biological threat, a highly transmittable and highly deadly virus, namely SARS-CoV-2. SARS stands for Severe Acute Respiratory Syndrome which comprise several influenza-like symptoms, such as fever, malaise, myalgia, headache, cough, and shivering (rigors). This virus outbreak has already affected 215 countries and territories and nearly 300.000 people have died (data from World Healt Organization). Given the severity of this outbrake, there is an urge to study this virus and develop effective treatment and preventive measures. In this article, I am going to review the major molecular characteristics of SARS-CoV-2 and ongoing research in treatments and vaccines.

Molecular biology of SARS-CoV-2

SARS-CoV-2, named by the International Comittee on Taxonomy of Viruses, is a novel member of coronaviruses. Thus, this virus consists on a RNA (ribonucleic acid) molecule encapsulated in a proteic envelope or capsid; the RNA molecule constitues the genetic material of he virus and encodes the information for the expression of viral proteins. In addition, the capside is surrounded by a spiky lipidic membrane, which originally belonged to the infected host cell. As a result, the virus has a spherical and crown-like morphology (see Fig. 1).

More in detail, the viral structure consists on four major structural proteins: spikes (S), envelope (E), membrane (M) and nucleocapsid (N). S, E and M proteins are anchored to the lipid layer and form the outer envelope of the virus; on the other hand, N proteins form the inner capsid which anchors the RNA genetic material.

Figure. 1. Transmission Electron Microscope (TEM) images fron the Center of Disease Control and Prevention | CS Goldsmith and TG Ksiazek (left) and NIAID (right).

SARS-CoV-2 phylogenetic analysis have revealed that this virus belongs to the Sarbecovirus subgenus and Betacoronavirus genus and it is distinct to SARS-CoV (virus responsible for the 2002 outbreak). Yet, these two viruses share many characteristics. For instance, the mechanism of infection is similar and occurs through the Angiotensin Converting Enzyme II (ACE II). ACE II is a protein expressed in many human tissues, such as in the lungs, arteries, intestines, heart and kidneys and its main function is the regulation of blood pressure. On the other hand, many coronaviruses bind this enzyme and enter the cell through this (Fig. 2).

The responsible for interacting and binding ACE II is the S viral glucoprotein, which is anchored to the lipid layer, as previously explained.

Figure 2. Life Cycle of Highly Pathogenic Human Coronaviruses (CoVs). https://doi.org/10.1016/j.it.2020.03.007

Once the viral RNA has entered the cell, it exploits host’s molecular machinery (ribosomes and amino acids) to synthesize viral proteins. First, replicase enzymes are produced, which trigger the duplication of the viral RNAs. As a result, thousands of RNA molecules are available to proceed with the viral infection.

Finally, viral structural proteins (S, E, M and N) are synthesized and delivered to the endoplasmic reticulum (ER), where proteins insert and assemble. N proteins attach the viral RNA and interact with membrane structural proteins (M), which mediated most of the protein-protein interactions for virion assembly. Virions bud the ER lipid membrane and wrap the capsid, thus mature virions are generated. Following assembly, virions are transported to the cell surface in vesicles and released by exocytosis.

How to fight against SARS CoV-2

We have just reviewed the reproductive cycle of the virus. Indeed, it is key to understand the viral proteins and mechanisms, in order to develop vaccines and therapeutics. Henceforth, we are going to explain the current state of the different drugs that are being developed against SARS CoV-2. These include neutralizing antibodies, antiparasitic drugs and other antiviral drugs

Neutralizing antibodies

The role of antibodies in the control of viral infection is unquestionable. Antibodies are normally produced naturally by immune cells, as a response to vaccines or infective virus. Studies have shown that upon viral infection most patients produce antibodies against the virus; moreover, the presence of antibodies increased since day-15 after onset. In contrast, viral presence decreased significantly during day 15-39. These results suggest that antibodies are effective in neutralizing the virus and that offers vital clinical information during the course of SARS-CoV-2 infection.

Hence, different configurations of antibodies are being developed, which differ in size and number of domains. All currently developed anti-SARS-CoV neutralizing antibodies target the viral S protein, at different recognition sites. Yet, these antibodies have not been proved to be effective in humans and much research must be done in this area.

Chloroquine

Chloroquine was first studied in 1960 for the treatment of mononucleosis. Although, the therapeutic effect of this drug is controversial, it has been well stablished that chloroquine is active against a wide range of virus in vitro. Chloroquine and hydroxychloroquine are both 4-aminoquinolines, a group of molecules that have been shown to be potential chemotherapeutics and antimalarian drugs.

The mechanism of action of chloroquine against virus is not yet completely elucidated, and their efficacy has been attributed to different mechanisms. For example, 4-aminoquinolines are weak bases and they increase the pH in cellular organelles; it is though that this change in pH may impair the activity of certain enzymes that are essential for viral activity. They may also affect the glycosilation of ACE II, thus altering the entry mechanism of the virus.

Hydroxychloroquine has been reported to inhibit SARS-CoV2 in vitro. At present, several clinical trials have been conducted in China and have reported a therapeutic effect of the drug. On going trials in other countries have reported different results, thus making the use of hydroxychloroquine controversial. Indeed, wide use of hydroxychloroquine is thought to expose some patients to rare but potentially fatal harms, including serious cutaneous adverse reactions, fulminant hepatic failure, and ventricular arrhythmias. 

Ivermectin

Ivermectin is an FDA-approved broad spectrum anti-parasitic agent, which has been reported to have potential antiviral activity. In previous studies, ivermectin has been shown to impair normal viral activity in a wide range of viruses, such as HIV, DENV 1-4, West Nile Virus, Venezuelan equine encephalitis virus (VEEV) and influenza. Furthermore, its therapeutic potential was observed in a clinical trial against DENV infection.

According to previous reports, ivermectin was thought to have antiviral potential against SARS-CoV2. Its mechanism of action is likely the inhibition of the nuclear transport; in other words, this drug may impair the transport of viral proteins to the nucleus, thus inhibiting the replication.

Because ivermectin FDA-approved and has an established safety profile for human use, it is a promising drug for COVID-19 treatment. Nonethless, no clinical trial has been conducted and thus more clinical evidence is needed.

Remesdivir

Remesdivir is a broad antiviral developed by Gilead Science. This drug was initially designed for the treatment of Ebola virus and Marburg virus infections; however, in clinical trial studies, it did not show any effectiveness against this viruses. Subsequently, remesdivir was studied in vitro against other viruses, and its antiviral activity was demonstrated for some filoviruses, pneumoviruses, paramyxoviruses and coronaviruses.

Remesdivir is a nucleotide analog that interferes with the activity of RNA-dependent RNA polymerases. Thus, this drug prevents the replication of viral RNA molecules and the reproduction of the viruses.

Since the outbreak of SARS-CoV2, remesdivir has been seen as the most promising treatment. Currently global clinical trials have demonstrated that this drug reduces recovery time in COVID-19 patients and has a significant benefit in survival.

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