Researchers review the origins of SARS-CoV-2 and present treatment methods

A million more questions arise for every answer we have against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Where did it come from? And will it ever go away? A recent article published in Frontiers in Cellular and Infection Microbiology reviews what scientists currently know about the origin, SARS-CoV-2 structure, and potential treatments against this new virus.

Study: SARS-CoV-2: Origin, Evolution, and Targeting Inhibition. Image Credit: Droneandy / Shutterstock
Study: SARS-CoV-2: Origin, Evolution, and Targeting Inhibition. Image Credit: Droneandy / Shutterstock

Origin of SARS-CoV-2

There are many schools of thought surrounding the origins of SARS-CoV-2. Some theories postulate SARS-CoV-2 evolved directly from another coronavirus called SARS-CoV. Others believe it was leaked from a laboratory in Wuhan, China, where the virus was first detected. The theory most supported by scientists, however, is that SARS-CoV-2 came from bats and jumped to humans.

Evolutionary analysis of SARS-CoV-2 and others in the coronavirus family suggest that SARS-CoV-2 is a new evolutionary branch of coronaviruses with only a 90% genetic similarity to SARS-CoV and less than 90% similarity to MERS-CoV.

The SARS-CoV-2 spike protein has more than a 98% genetic similarity to the bat coronavirus RaTG13. Moreover, the bat RaTG13 and SARS-CoV-2 can identify angiotensin-converting enzyme 2 (ACE2), and both retain the Leu455 residue, which helps with recognizing ACE2 —indicating strong support for the bat hypothesis.

SARS-CoV-2 features for viral entry

SARS-CoV-2 spans 100 nm with several proteins —the membrane (M), envelope (E), spike (S), and nucleocapsid (N) proteins, an accessory protein, and non-structural proteins. The spike protein, a type I transmembrane glycoprotein, helps with viral entry and membrane fusion of host cells.

The coronavirus enters the cell in two ways. The direct approach involves targeting cells and occupying ACE2 on the membrane to block signals and disturb the renin-angiotensin system. The second approach is to promote immune system dysfunction. By binding to ACE2, the virus increases inflammatory markers such as IL-1 and reduces immune cells.

Upon entering the host cell, viral RNA attaches to the host cell’s ribosome to create two large coterminal polyproteins. These proteins are later broken down into several pieces where they will package new virions. Two proteases involved in this process are the papain-like protease and the coronavirus main protease. RNA polymerase is also used to replicate the coronavirus’s genetic material.

Interfering with any of these processes could prove to be an effective antiviral strategy.

SARS-CoV-2 spike protein structure

The spike protein operates in an ‘open’ and ‘closed’ state. Changes between the two structures may help with binding to the host receptor ACE2. For membrane fusion between virus and host cell, the spike protein rearranges its structure with the closed state having all three receptor-binding domains (RBDs) in a ‘down’ conformation near the trimer’s central cavity.

Thus, it is expected that the opening of the SARS-CoV-2 RBD is essential for interacting with ACE2 and triggering changes of conformation. The opening of RBD results in cleaving the S2 site, fusing membrane, and entering into cells,” wrote the researchers.

The overall structure of the SARS-CoV-2 spike protein is similar to the spike protein of SARS-CoV.

When binding with ACE2, the residues of the RBD is critical in forming connections with the ACE2’s N-terminal helix. Structural changes in the RBD and interactions between ACE2 and the RBD are two main factors for infection.

Preventing SARS-CoV-2 infection

One of the focuses for blocking COVID-19 infection is to target the spike protein’s interaction between ACE2 and the RBD. A growing body of evidence points to neutralizing antibodies as an effective method for inhibiting SARS-CoV-2.

While there’s currently no effective drug to prevent the spread of SARS-CoV-2, developing inhibitors that block membrane fusion between the virus and its potential host could help. Coronavirus fusion inhibitors, such as EK1 and its derivative EK1C4, have shown promise in inhibiting SARS-CoV-2 by targeting the S2 subunit.

Inhibitors blocking ACE2 have also been considered. By blocking ACE2, you prevent the spike protein from occupying it and potentially avoid infection. ACE2 inhibitors such as captopril, enalapril, and lisinopril have been under study. However, ACE2 inhibitors may be a double-edged sword. While it could prevent inflammation, there’s a risk it could improve viral entry as many potential ACE2 inhibitors acts on the peptidase domain of ACE2, not on the interface where SARS-CoV-2 binds.

Inhibitors blocking the enzymatic activity of Mpro can prevent the maturation of viral proteins, making it a favorable target for drug development. Some notable Mpro inhibitors are boceprevir, GC-376, and calpain/cathepsin.

Remdesivir also shows promise as an antiviral drug against several RNA viruses, including SARS-CoV-2. By inhibiting RNA-dependent RNA polymerase, it can obstruct COVID-19 infection. Others, including galidesivir, ribavirin, favipiravir, and EIDD-2801, have a similar mechanism of action, with EIDD-2801 being 3 to 10 folds more effective than remdesivir in inhibiting viral replication.

Journal reference:
Jocelyn Solis-Moreira

Written by

Jocelyn Solis-Moreira

Jocelyn Solis-Moreira graduated with a Bachelor's in Integrative Neuroscience, where she then pursued graduate research looking at the long-term effects of adolescent binge drinking on the brain's neurochemistry in adulthood.

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