Protein sequences have been discovered which facilitate the entry of the Covid-19 virus into human cells. Aela O’Flynn learns what this means for us, and how these proteins could form the basis of anti-COVID drug treatment.

By Aela O'Flynn | Feb 24 2021

We've heard about the virus, we've heard about the vaccines, but we have heard very little about any potential treatment for COVID-19. The vaccine was the first and most important step to stem the spread of COVID. As vaccination programmes are rolled out across the globe to prevent the infection, science can now turn its attention towards finding more effective measures to treat those who are infected by SARS-CoV-2.

Professor Denis Shields of Clinical Bioinformatics at UCD has recently published an exciting paper that could accelerate our ability to do just that. As part of an international research group, Professor Shields identified proteins that aid the entry of SARS-CoV-2 into cells, allowing them to infect human hosts. Knowledge of these proteins could now be used to develop a targeted anti-COVID drug therapy.

To develop a new drug for COVID-19 that is effective, safe, and approved for use across international borders is complicated, to say the least. Drug development can take years, and even decades, before reaching manufacture and distribution to market. For this reason, therapeutic trials during the pandemic have focused on repurposing drugs currently authorised to treat other diseases, such as Remdesivir, an anti-viral drug for Ebola, and Baricitinib, a drug used to treat rheumatoid arthritis.

It is unlikely that any new drugs developed as a result of Dr Shield's research will be used to treat COVID-19 patients during the current pandemic. However, drug development now could play an extremely important role in future-proofing against future, inevitable pandemics. Dr Mike Ryan, head of the WHO Emergency Response, told us late last year that this pandemic is "not necessarily the big one". To protect ourselves, infrastructure and science must prepare not just for this pandemic, but for those that are yet to come.

SARS-CoV-2, the virus, causes COVID-19, the disease, by binding to proteins on the cell surface that allow it to enter the cell and hijack cell machinery to produce copies of itself. Once the virus replicates, it goes on to infect other cells, and the cycle continues. Professor Shields and the research team used powerful computer analysis to identify what proteins facilitate SARS-CoV-2 viral entry into human cells. The identification of these proteins can tell us about the spread of COVID-19 in the body, how it enters cells and replicates, and the kind of cells it prefers to attack. It also establishes potential targets for anti-Covid drugs. If we can block these proteins and prevent the virus from entering cells, we limit the ability of COVID to take hold of its host.

The paper has identified a number of proteins on host cells that allow the virus to enter cells, as well as patterns of amino acids called “short linear motifs” that enable proteins to communicate with each other. These "short linear motifs", or SLiMs, come into play inside the cell, and enable the virus to gain control of the cell’s equipment and use it for its own purposes. The virus depends on both mechanisms to mount its attack.

Now that these proteins and SLiMs have been identified, Professor Shields and his team will design mimic peptides that are structurally identical to the original proteins and SLiMs, but block the entry of SARS-CoV-2 into cells, rather than permitting it. These will then be recreated in a lab and tested to see if they can, in reality, prevent the virus from entering cells. This new project, led by Professor Denis Shields in collaboration with Dr Marc Devocelle, Associate Professor of Chemistry at RSCI, and Dr Virginie Gautier, Associate Professor of Virology at UCD, has been funded by the Science Foundation of Ireland and is currently ongoing.

Shields describes the project as bringing “together three UCD and RSCI research teams in computational biology, virology and peptide chemistry”. Professor Shield’s role is to design the peptide mimics. Dr Devocelle will then manufacture the designed peptides in a lab. Finally, Dr Gautier will test these manufactured peptides to study how they behave, and how they respond to different molecules and potential therapies. The Centre for Experimental Host Pathogen Research, the lab where the peptides will be tested, has been enhanced to achieve level three biosafety clearance due to the risk associated with studying COVID-19 molecules. This multi-step research is a true collaboration across individuals, disciplines, universities, and campuses, and could play a major role in the response to pandemics present and future.

Research taking place both internationally, and right here on the UCD campus, has significant potential to inform our treatment not only of COVID-19, but also of emerging viruses that we will face in the coming years and decades. While this may not be "the big one", the coronavirus pandemic has created space for science and technology to accelerate, to collaborate, and to educate in a way that barely seemed possible just one year ago. Pay attention to the hum of scientific activity on campus, because the UCD research community is certainly not shying away from the challenges and opportunities that come with this new scientific frontier.