While some scientists seek a vaccine against the novel coronavirus (SARS-CoV-2), others try to understand the virus’s entry mechanism. For months Prof. David Alsteens's laboratory team has been trying to answer two questions: How does SARS-CoV-2 enter our cells and how can it be prevented from doing so? Their answers are promising.
The virus on everyone's lips at the moment, even behind our masks, remains without a vaccine. All over the world, the race is on to find the panacea to end the COVID-19 pandemic. Meanwhile, some scientists are contributing to the quest by trying to better understand how the virus behaves. Among them, the laboratory team of Prof. Alsteens, an FNRS research associate at UCLouvain’s Louvain Institute of Biomolecular Science and Technology (LIBST), has worked tirelessly since March to understand the molecular-level interaction between the coronavirus and our cells. Their study’s promising results have just been published in Nature Communications.
Finding the key to the lock
‘For this research on the coronavirus,’ Prof. Alsteens explains, ‘we’d already gained several years of expertise concerning the molecular mechanisms of infections. This saved us a lot of time.’ In fact, for the past five years, he and his team at the NanoBiophysics Lab have been studying the interactions between viruses and cells on a nanometric scale. How does a virus interact with a cell in order to bond with it? How is the cell made permissive to the virus? How, subsequently, does the infection start? In short, how does the very first contact between the virus and the cell surface take place? For some very specific viruses such as reovirus, Prof. Alsteens's team understands the mechanisms. ‘To enter the cell, the reovirus must insert a key into a lock in the cell. This usually folded key is unfolded at some point in the infection by a sugar called sialic acid.’ And what about the coronavirus? ‘The same research remained to be done to find this key in the hope of blocking the interaction and preventing the spread of infection.’
What’s the affinity between virus and cell?
In late 2019, the new coronavirus arrived. By early 2020, it was at the gates of Europe. By March 2020, Prof. Alsteens and his laboratory team decided to apply their knowledge and skills to fighting it (see ‘Lock the door on coronavirus’). ‘We first worked on isolated proteins recovered from the surface of viruses and cells,’ he says. ‘We observed how these two molecules interacted.’ To do this, the laboratory team used atomic force microscopy (AFM), a valuable biophysical tool, which has already enabled them to unlock scientific secrets. ‘The atomic force microscope works like a vinyl record player. Its very fine tip is placed in contact with a sample and wanders over it. Point by point, we can draw an image of the sample’s surface.’ In the case of SARS-CoV-2, scientists attached the coronavirus protein (called S1) to the AFM tip and brought it to the cell surface protein (also called a receptor) ACE2. They let them interact, then pulled on each to test their resistance. ‘In molecular biology, we speak more precisely of affinity, that is, the attraction that receptors and their ligands have for each other,’ Prof. Alsteens adds. His team thus took measurements of the strength of all the anchoring bonds between the virus and the cell, quantified the number of bonds as well as their dynamics. The objective was to understand how the coronavirus can attach itself optimally to the cell surface in order to send a signal to the cell that it can enter.
Especially strong interaction
‘After taking all of these steps, it became clear that the S1 protein receptor binding domain (RBD) was predominant in the interaction. On its own, it was responsible for this strong interaction and is therefore the key element allowing the virus to enter cells and lead to infection,’ Prof. Alsteens explains. ‘As this interaction between the S1 protein and the ACE2 receptor was significant, we decided to characterise it by extracting their biophysical properties through an in vitro study on purified molecules.’ The laboratory thus discovered not only the important role of ACE2 receptors, but also other receptors such as sialic acids and integrins.
Hope for a COVID-19 drug
Now that the team knows more about the interaction between virus and cell, hopes are high. ‘We’re currently testing inhibitors of this interaction. In other words, we’re trying to develop molecules that would lessen the interaction and thus the infection’s impact.’ Such a drug would be an interesting alternative to vaccines. ‘The drug could be preventive for people at risk or used in the acute phase in infected patients to prevent contamination of other cells.’ In the hope of creating a drug, the NanoBiophysics Lab team is continuing its work by injecting small fragments of the ACE2 protein when the virus attaches to the surface of cells. The fragments compete with the interaction. Are they able to prevent the coronavirus from entering the cell? We don’t know yet. But this UCLouvain laboratory intends to find out while searching for other receptors involved in interactions.
>>See also : 'Lock the door on coronavirus'
A glance at David Alsteens' bio
David Alsteens is an FNRS research associate at the Louvain Institute of Biomolecular Science and Technology (LIBST), and leader of the UCLouvain NanoBiophysics Lab. He holds a master's degree in chemical engineering and bio-industry and a PhD in bioengineering, obtained in 2007 and 2011 respectively from UCLouvain. Currently a professor in UCLouvain’s Faculty of Bioengineering, he also spent two years at the Swiss Federal Institute of Technology in Zurich, Switzerland, between 2013 and 2015. His research focuses on the study of interactions between viruses and cells, and has been funded mainly by an ERC Starting Grant (Europe) in 2017, Welbio funding (Walloon Region) in 2019, and FNRS and UCLouvain funding.
© Binding of the coronavirus spike protein(red) to an ACE2 receptor (blue) on a human cell leads to the penetration of the virus in the cell, as depicted in the background., selvanegra, iStock