What are spike proteins?

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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the virus causing the global outbreak of COVID-19 disease. One of the main biological characteristics of SARS-CoV-2, as well as several other viruses, is the presence of advanced proteins that allow these viruses to enter host cells and cause infection.

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An overview of the structure of the coronavirus

Coronaviruses (CoV) like Middle East Respiratory Syndrome (MERS) -CoV, which had infected nearly 2,500 people by the end of 2019, as well as the new severe acute respiratory syndrome (SARS) -CoV-2, are enveloped viruses and spherical. which typically measure between 80 and 120 nanometers (nm).

The coronavirus RNA genome, which with a median length of 29 kb is the longest of all RNA viruses, is made up of six to ten open reading frames (ORFs) which are responsible for encoding both the replicase and structural proteins of the virus.

Each of the components of the viral genome is packaged in a helical nucleocapsid surrounded by a lipid bilayer.

The viral envelope of coronaviruses is generally made up of three proteins which include the membrane protein (M), the envelope protein (E) and the spike protein (S).

Structure of the coronavirus

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Spike protein functions

Protein S is a large, highly glycosylated type I transmembrane fusion protein consisting of 1160 to 1400 amino acids, depending on the type of virus.

Compared to the M and E proteins which are mainly involved in the assembly of the virus, the S protein plays a crucial role in the penetration of host cells and the initiation of infection.

Notably, the presence of S proteins on coronaviruses is what gives rise to the spike-shaped protuberances found on their surface.

The S proteins of coronaviruses can be divided into two important functional subunits, which include the N-terminal S1 subunit, which forms the globular head of the S protein, and the C-terminal S2 region which forms the stem of the protein and is directly integrated into the viral envelope.

When interacting with a potential host cell, the S1 subunit will recognize and bind to receptors in the host cell, while the S2 subunit, which is the most conserved component of S protein, will be responsible for the fusion of the envelope of the virus with the membrane of the host cell.

How protein S allows coronaviruses to enter cells

Once the S1 subunit binds to receptors in the host cell, two major conformational changes must occur for the S2 subunit to complete fusion of the virus to the cell membrane. The two components of the S2 subunit involved in coronavirus fusion include heptadic repeat (HR) regions one and two, otherwise referred to as HR1 and HR2.

The first conformation otherwise called pre-hairpin, involves the transformation of an unstructured linker within the S2 subunit to become helical. The second conformational change to occur involves the inversion of helix C from this subunit to the coil, resulting in the formation of a bundle of six helices.

Once these conformations are complete, the fusion peptide is anchored to the membrane of the host cell to allow the virus to approach the cell membrane and optionally to deliver the nucleocapsid to the target cell.

Targeting viruses via the S protein

Without the S protein, viruses like the new SARS-CoV-2 would not be able to interact with cells of potential hosts like animals and humans to cause infection. As a result, protein S represents an ideal target for vaccine and antiviral research efforts.

In addition to its role in cell penetration, the S protein of viruses, in particular the SARS-CoV-2 virus, is a major inducer of neutralizing antibodies (NAbs). NAbs are protective antibodies that are naturally produced by our humoral immune system.

To trigger their antiviral activity, NAbs bind to the surface epitopes of viral particles to prevent their entry into a host cell. Some of the NAbs that have been identified against SARS-CoV include 80R, CR3014, and CR3022, all of which specifically target the S1 domain.

The sensitivity of the S protein of SARS-CoV-2 to these NAbs has led many researchers to be interested in the development of standardized agents capable of blocking the binding and fusion of the S protein of SARS-CoV-2 to cells. hosts.

Although a recent study found that the ability to neutralize CR3022 against the SARS-CoV-2 region binding domain (RBD) within the S1 subunit is uncertain, another study on Ebola viruses and SARS revealed that a cocktail of NAbs has a stronger neutralizing abilities compared to when these NAbs are administered alone.

This information therefore leads researchers to believe that a combination of several potent NAbs has the potential to target SARS-CoV-2 and increase its sensitivity to neutralization.

The references

  • Belouzard, S., Millet, JK, Licitra, BN and Whittaker, GR (2012). Coronacirus cell entry mechanisms mediated by viral spike protein. Virus 4(6); 1011-1033. doi: 10.3390 / v4061011.
  • Wang, Q., Wong, G., Lu, G., Yan, J. and Gao, GF (2016). Advanced MERS-CoV protein: targets for vaccines and therapeutics. Antiviral research 133; 165-177. doi: 10.1016 / j.antiviral.2016.07.015.
  • Zhou, G., & Zhao, Q. (2020). Perspectives on therapeutic neutralizing antibodies against the novel coronavirus SARS-CoV-2. International Journal of Biological Sciences 16(ten); 1718-1723. doi: 10.7150 / ijbs.45123.

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