New polypeptide can provide universal protection against coronaviruses

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

The SARS-CoV-2 virus is the agent responsible for the persistent coronavirus disease 2019 (COVID-19), and the peak protein is the main structure on which the virus relies for access to host cells.

Importantly, the inhibitor was effective against the proteins of other coronaviruses, including SARS-CoV-1 and the Middle Eastern Respiratory Syndrome CoV (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 appear in the future.

“We expect the inhibitor reported here to be a valuable tool in ending the COVID-19 pandemic,” wrote Jianpeng Ma and colleagues at Baylor College of Medicine in Houston, Texas.

A preview version of the research article is available on the bioRxiv* server, while the article is being peer-reviewed.

Coronaviruses have been a major threat for two decades

Within just the past twenty years, three coronaviruses have posed a significant threat to public health, causing local and global outbreaks of potentially life-threatening respiratory disease.

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 virus. 2 virus responsible for the ongoing Covid19 pandemic.

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

The emergence of variants means that new approaches are urgently needed

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

Subunit 1 (S1) is the main target for neutralizing antibodies after natural infection or vaccination, and therefore there is a constant positive choice for immune flight variants. Subunit 2 (S2), on the other hand, is more conserved between different coronavirus strains.

Since SARS-CoV-2 was identified at the end of December 2019 in Wuhan, China, its unprecedented distribution has led to the emergence of several variants containing extensive mutations in the ear protein.

Some of these variants show a tighter binding to ACE2 and increased transmissibility, as well as partial resistance to neutralization of antibodies by sera from vaccines or repairers.

“With more than 130 million confirmed cases and widespread vaccination around the world, the emergence of new SARS-CoV-2 variants could be accelerated,” said Ma and colleagues. “New drugs that are not susceptible to mutations are therefore urgently needed.”

The concept behind the current study

Following the introduction of host cells, the SARS-CoV-2 genome leads to the synthesis of new vein proteins. The proteins are then folded, assembled and translocated for interaction with newly replicated genomic RNA to generate new virions.

Mom and colleagues assumed that foldable fragments of the ear protein such as polypeptides derived from S2 would form non-native oligomers with wild-type spikes. This will reduce the level of the native peak on the envelope of newly generated virions and potentially harm their infectivity, the team says.

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

What did the study find?

Transfection of the cells with SARS-CoV-2 plasmid containing spikes yielded a high expression of cleaved vein proteins throughout the cell lysate.

When the F1-nurturing plasmid was co-transfected with the spike-nurturing plasmid, the point S2 was almost completely reduced in the whole cell lysate and in the cell surface fraction.

“Thus, F1 strongly interfered with the expression and translation of the cell surface of SARS-CoV-2 peak,” say 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 reduced in the whole cell lysate and the cell surface fraction.

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

The drug can be effective against coronaviruses over a long period of time ‘

“The high potential of F1 to influence the expression and surface translocation of nail glycoproteins by coronaviruses that caused severe outbreaks or pandemics between 2002 and 2021 indicates that F1 has the promise of being an effective therapeutic agent against various coronavirus lines over a long period of time. to become. period, ”write the researchers.

Since the sequences corresponding to the F1 polypeptide are highly conserved between SARS-CoV-2 variants, it can be expected that this inhibitor will be effective against the peak proteins of almost any variant that will emerge in the future.

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

* Important notice

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