New polypeptide could provide universal protection against coronaviruses

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

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

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

In addition, the researchers say the polypeptide inhibitor – called F1 – is expected to be effective against the spike proteins of nearly all SARS-CoV-2 variants that may appear in the future.

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

A preprinted version of the research paper is available at bioRxiv server, while the article is under peer review.

Coronaviruses have been a major threat for two decades

Only in the past 20 years did three coronaviruses pose a significant threat to public health, triggering regional and global outbreaks of potentially life-threatening respiratory diseases.

These include the SARS-CoV-1 virus responsible for the SARS outbreak from 2002 to 2003, the MERS-CoV virus that has caused several outbreaks in the Middle East since 2012, and the new SARS-CoV-2 virus responsible for the ongoing Covid19 pandemic.

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

The emergence of variants means that new approaches are urgently needed

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

Subunit 1 (S1) is the major target of neutralizing antibodies after natural infection or vaccination and is therefore under constant positive selection for immune escape variants. In contrast, subunit 2 (S2) is more conserved between different strains of coronavirus.

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

Some of these variants showed stronger binding to ACE2 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 vaccinations around the world, the emergence of new escape SARS-CoV-2 variants could be accelerated,” said Ma and colleagues. “New therapies that are insensitive to mutations are therefore urgently needed.”

The concept behind the current study

Upon entry into the host cell, the SARS-CoV-2 genome guides the synthesis of new spike proteins. The proteins are then folded, assembled, and translocated to interact with newly replicated genomic RNA to generate new virions.

Ma and colleagues hypothesized that foldable fragments of the spike protein, such as polypeptides derived from S2, would form non-native oligomers with wild-type spikes. This would reduce the native spike level on the envelope of newly generated virions and potentially reduce their infectivity, the team said.

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

What did the study find?

Transfection of the cells with SARS-CoV-2 spike host plasmid yielded high expression of cleaved spike proteins in the whole cell lysate.

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

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

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

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

It could be effective against coronaviruses for ‘a long time’

“The high potency of F1 in disrupting expression and surface translocation of the peak glycoproteins of coronaviruses that caused severe outbreaks or pandemics between 2002 and 2021 suggests that F1 holds great promise to become an effective therapeutic agent against a variety of coronavirus. lines for a long time. period ”, the researchers write.

In addition, since the sequences corresponding to the F1 polypeptide are highly conserved between SARS-CoV-2 variants, this inhibitor can be expected to be effective against the spike proteins of almost all variants appearing in the future. them to it.

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

*Important announcement

bioRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, serve clinical practice / health-related behavior, or be treated as established information.