The new polypeptide could provide universal protection against coronaviruses

U.S. researchers have developed a spike protein inhibitor found in 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 newly generated virions.

The SARS-CoV-2 virus is the agent responsible for the ongoing pandemic of coronavirus disease 2019 (COVID-19) and the ear protein is the main structure on which the virus is based for cell entry. · Host cells.

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

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

“We hope the inhibitor reported here is 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 preprinted version of the research work is available at bioRxiv* server, while the article is undergoing a peer review.

Coronaviruses have posed a major threat for two decades

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

These include the SARS-CoV-1 virus responsible for the SARS outbreak from 2002 to 2003, the MERS-CoV virus which has caused several outbreaks in the Middle East since 2012 and the new SARS-CoV-2 virus which is responsible for the Covid pandemic19.

Researchers are currently competing to develop vaccines based on the SARS-CoV-2 ear protein that will generate immune responses against wild ear after a natural infection with the virus.

The emergence of variants makes new approaches urgently needed

Once the SARS-CoV-2 tip protein binds to the host cell receptor, the angiotensin converting enzyme 2 (ACE2), the spike divides into two subunits.

Subunit 1 (S1) is the primary target of neutralizing antibodies after a natural infection or vaccination and is therefore constantly selected for immune escape 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 the emergence of several variants harboring extensive mutations in the ear protein.

Some of these variants have shown closer 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 vaccination worldwide, the emergence of new escape SARS-CoV-2 variants could be accelerated,” says Ma and colleagues. “Therefore, new therapeutics insensitive to mutations 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 ear proteins. Proteins fold, assemble, and move for interaction with newly replicated genomic RNA to generate new virions.

Ma and colleagues hypothesized that folding fragments of spike protein, such as S2-derived polypeptides, would form non-native oligomers with wild-type spikes. This would reduce the level of the native ear in the envelope of the newly generated virions and could affect their infectivity.

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

What did the study find?

Transfection of the cells with a plasmid containing SARS-CoV-2 peaks produced high expression of cleaved ear proteins throughout the cell lysate.

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

“Therefore, F1 strongly interfered with the expression and translocation of the cell surface of the SARS-CoV-2 ear,” says 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 tip proteins. Again, S2 was reduced almost completely to the entire cell lysate and to the cell surface fraction.

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

The agent could be effective against coronaviruses for “a long period of time”

“The high potency of F1 in interfering with the expression and surface translocation of coronavirus tip glycoproteins that caused severe outbreaks or pandemics between 2002 and 2021 suggests that F1 has a high promise of becoming an agent. effective therapeutic against different coronavirus lineages for a long time point, ”the researchers write.

In addition, 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 almost any variant that appears in the future, they add.

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

* Important news

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