The new polypeptide could provide universal protection against coronaviruses

Researchers in the United States have developed a spike protein inhibitor found on the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that limits its formation in host human cells that would otherwise be the source of the newly generated virions.

The SARS-CoV-2 virus is the agent responsible for the ongoing coronavirus disease pandemic 2019 (COVID-19), and the spike protein is the main structure on which the virus is based for host cell entry.

Importantly, the inhibitor was effective against the peak proteins of other coronaviruses, including SARS-CoV-1 and Middle East CoV respiratory syndrome (MERS-CoV).

Furthermore, the researchers say that the polypeptide inhibitor – called F1 – is expected to be effective against the peak proteins of almost any SARS-CoV-2 variant that may occur in the future.

“We expect the inhibitor reported here to be an invaluable aid in helping to end the COVID-19 pandemic,” writes Jianpeng Ma and colleagues at Baylor College of Medicine in Houston, Texas.

A pre-printed version of the research paper is available on bioRxiv* server, while the article is subject to peer review.

Coronaviruses have been a major threat for two decades

In the last 20 years alone, three coronaviruses have posed a significant threat to public health, causing regional and global outbreaks of potentially life-threatening respiratory diseases.

These include the SARS-CoV-1 virus responsible for the SARS outbreak 2002-2003, the MERS-CoV virus that caused various outbreaks in the Middle East since 2012 and the novel SARS-CoV-2 virus that is responsible for the Covid19 pandemic.

Currently, researchers are struggling to develop vaccines based on the SARS-CoV-2 peak protein that will generate immune responses against wild-type peak following natural infection with the virus.

The emergence of variants means that new approaches are urgently needed

Once the SARS-CoV-2 peak protein binds to its host cell receptor – the angiotensin 2 converting enzyme (ACE2) – the peak is cleaved into two subunits.

Subunit 1 (S1) is the main target of neutralizing antibodies after natural infection or vaccination and is therefore permanently selected positively for immune evacuation variants. Subunit 2 (S2), on the other hand, is more conserved among different coronavirus strains.

Since SARS-CoV-2 was first identified in Wuhan, China, in late December 2019, its unprecedented spread has led to several variants harboring extensive mutations in the spike protein.

Some of these variants showed closer ACE2 binding and increased transmissibility, as well as partial resistance to antibody neutralization by sera from vaccinated or convalescent individuals.

“With more than 130 million confirmed cases and widespread vaccination worldwide, the emergence of new SARS-CoV-2 evacuation variants could be accelerated,” says Ma and colleagues. “New mutation-insensitive therapies are urgently needed.”

The concept behind the current study

Following the entry of host cells, the SARS-CoV-2 genome guides the synthesis of new spike proteins. The proteins are then folded, assembled, and translocated for interaction with newly reproduced genomic RNA to generate new virions.

Ma and colleagues hypothesized that foldable fragments of the spike protein, such as S2-derived polypeptides, would form non-native oligomers with wild-type tips. This would reduce the level of the native peak on the envelope of newly generated virions and could affect their affectivity, the team says.

The researchers synthesized a polypeptide called F1 that contained part of the S2 sequence of the SARS-CoV-2 protein. They then tested its impact on the expression and translocation of the cell surface of the peak proteins to the surface of the host cell in the human HEK293T cell line.

What did the study find?

Transfection of cells with peak-containing SARS-CoV-2 plasmid resulted in elevated expression of cleaved spike proteins throughout the cell lysate.

When the F1 port plasmid was co-transfected with the peak port plasmid, the S2 peak was almost completely diminished in the entire cell lysate and in the cell surface fraction.

“Thus, F1 strongly interfered with the expression and translocation of the cell surface of the SARS-CoV-2 peak,” says Ma and colleagues.

Although F1 was derived from the SARS-CoV-2 sequence, the inhibitor was equally effective against the peak proteins of SARS-CoV-1 and MERS-CoV. Again, S2 was almost completely diminished in the entire cell lysate and cell surface fraction.

The identity of the amino acid sequence divided between these different coronavirus peaks was up to 35%, suggesting that F1 could be extremely resistant to mutations in the peak sequences of newly emerging SARS-CoV-2 variants.

The agent may be effective against coronaviruses over a long period of time

The high potency of F1 in interfering with the expression and surface translocation of peak glycoproteins from coronaviruses that caused severe outbreaks or pandemics between 2002 and 2021 suggests that F1 has a high promise of becoming an effective therapeutic agent against various coronavirus lines over a long period of time. of time. period “, write the researchers.

Moreover, since the sequences corresponding to the F1 polypeptide are highly conserved among SARS-CoV-2 variants, this inhibitor can be expected to be effective against the peak proteins of any variants that occur in the future, they add.

“We expect the inhibitor reported here to be an invaluable aid in the effort to stop the COVID-19 pandemic,” the team concludes.

*Important Note

bioRxiv publishes preliminary scientific reports that are not evaluated by colleagues and therefore should not be considered conclusive, guide clinical practice / health-related behavior or treated as established information.