How SARS-CoV-2 hijacks human cells

Disease and treatment 3. dec 2021 3 min Associate Professor Thomas Kruse Written by Kristian Sjøgren

New research shows how SARS-CoV-2 binds to proteins in human cells to disable the immune system and make copies of its own genome. The researchers behind the discovery have already developed a peptide that can potentially break that bond and be used as a drug.

Thousands of people die with COVID-19 each day, but fortunately, researchers are also becoming increasingly more knowledgeable on how to prevent this from happening.

So far, research has resulted in both vaccines and antiviral drugs, and now researchers have found a new way to suppress SARS-CoV-2.

The international research team has shown how SARS-CoV-2 binds to the proteins in human cells and what it gains from this.

The same research also elucidates how a small protein can disrupt the interaction between SARS-CoV-2 and human cells and thereby defeat the virus.

The research has been published in Nature Communications.

“This knowledge will benefit drug developers who are trying to tame COVID-19. They can now see how SARS-CoV-2 binds to proteins in human cells and how to disrupt this interaction. Using this knowledge, they can develop a drug much more rapidly that can be used to combat the pandemic,” explains a lead author behind the study, Thomas Kruse, Associate Professor, Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.

Thomas Kruse carried out the research in Jakob Nilsson’s laboratory in close collaboration with Matthias Mann’s Clinical Proteomics Group and several research groups in Sweden.

More drugs targeting COVID-19 still required

Although good vaccines have been developed to minimise the risk of COVID-19, focusing on developing more drugs is still required.

Vaccination does not ensure full immunity for many people. For example, older people and people with weakened immune systems may not produce the necessary antibody response to keep the virus at bay and may still experience severe breakthrough infections.

Further, SARS-CoV-2 strains are probably still mutating, eliminating the certainty that current vaccines will combat future variants.

A backup plan is thus required in the form of drugs that can combat SARS-CoV-2 once it has penetrated the body.

The new study shows what happens when SARS-CoV-2 strains enter the body.

SARS-CoV-2 has only one purpose

Thomas Kruse and colleagues investigated which cellular host proteins SARS-CoV-2 strains bind to when it penetrates human cells.

All viruses that infect humans have only one purpose: to replicate themselves.

However, viruses do not have all the molecular machinery to duplicate their genomes or make proteins based on the genetic code, so they instead hijack host proteins to do it for them.

When viruses have forced cells to make more and more viruses, at some point the cells are so full of viruses that they burst and viruses erupt into the environment. Then they can enter new cells and start the whole process all over again.

“We determined which human proteins SARS-CoV-2 binds to and takes over to make copies of itself,” says Thomas Kruse.

Using smart technology

The researchers used a technology called proteomic peptide phage–phage display (ProP-PD).

Phages are viruses that infect bacteria.

Using ProP-PD, the researchers cut all the proteins from the virus into small fragments and pasted each fragment onto a unique and tagged phage.

Then they tested which fragments bind to human proteins to determine very precisely how SARS-CoV-2 takes over these proteins.

“Our partners in Sweden developed this technique, which can map very precisely where on a human protein a virus binds,” explains Thomas Kruse.

SARS-CoV-2 binds to specific proteins

The results show that SARS-CoV-2 binds to a protein called G3BP and also show how this interaction occurs. G3BP is usually involved in cellular stress response in connection with combating viruses.

By binding to G3BP, SARS-CoV-2 eliminates part of the cellular defence mechanism and uses the protein to amplify its own genome, a win-win situation.

Producing potential drug candidates

The researchers then set out to develop a molecule that could disrupt the interaction between G3BP and SARS-CoV-2 and thus be a possible drug candidate to treat people already infected.

Thomas Kruse says that, once the researchers know where and how viruses bind, developing peptides to disrupt the interaction between viruses and the body’s proteins is not very complicated.

“This is the strength of ProP-PD, since it provides exactly the knowledge needed to carry out research that can be quickly tested in the laboratory,” he says.

The researchers developed a superpeptide that binds to the same part of G3BP, thereby competing with the virus for access to this protein.

Then they tested it on cells infected with SARS-CoV-2. They found that the peptides did exactly what they were designed to do: prevent SARS-CoV-2 from binding to G3BP and making copies of itself in the cells.

“This proof-of-concept study demonstrates that we have not only identified how SARS-CoV-2 binds to proteins in human cells but also how to disrupt the interaction. We will continue to work on this,” explains Thomas Kruse.

Thomas Kruse says that they are preparing the first animal experiments but would like pharmaceutical companies with greater financial resources than academia to take the discovery and use it to design drugs more quickly to benefit people with COVID-19.

“Pharmaceutical companies are probably much better geared up to develop a drug more rapidly than we are,” he concludes.

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