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Research, published in Science, looked at a possible ‘druggable pocket’ in the structure of the SARS-CoV-2 virus spike.
Prof Stephen Evans, Professor of Pharmacoepidemiology, London School of Hygiene & Tropical Medicine, said:
“This is certainly very interesting basic science from a group with a good reputation, and they have found something unusual about the virus that might be helpful to drug developers.
“It does not offer the prospect of a rapid production of a drug that would be able to stop Covid-19 in the near future.
“It is certainly not showing a drug that has been clinically tested, and the suggestion that it is relevant to remsdesivir must be taken with the fact that remdesivir, while working to a moderate degree in the early stages of disease to reduce its severity, has not shown really strong reductions in mortality.
“The cost of any new drugs is likely to be very high and take quite a long time to develop, possibly a longer timescale than for vaccines because it would probably not build as easily onto existing drugs as the vaccines have built on existing vaccines.
“The particular features of Covid-19 that involve coagulation may be relevant to the impact of linoleic acid, but neither SARS(1) nor MERS seems to have those effects so more work will be needed to understand mechanisms.
“It may well be important, but it is too early to be certain that it can be translated into clinical benefit for patients, but it is clearly a very good step forward in understanding.
“If Covid-19 becomes a disease that is not able to be eradicated or brought under control by vaccination and other protective measures, this may offer hope for that longer term future.”
Prof Nicola Stonehouse, Professor in Molecular Virology, University of Leeds, said:
“One of the concerns regarding controlling the current SARS-CoV-2 pandemic is the lack of antiviral drugs that specifically target the virus. This detailed study defines a pocket in the spike and hence generates very useful data as this could lead to the design of antiviral drugs in the future. However, it should be noted that the material used here was made in insect cells, which might be a limitation, and that drug design/screening would be needed in order to select candidate drugs, but it’s a very positive step in the right direction.”
Dr Michael Skinner, Reader in Virology, Imperial College London, said:
“This study started as an exercise to produce recombinant SARS-COV-2 spike protein in the test tube for studies on how it binds to cells in the respiratory tract (so that the virus can enter the cell) and to antibodies produced by our immune system in response to infection or vaccination. The protein was successfully produced and then subjected to intense scrutiny, including analysis of its molecular structure by the relatively recent technique of Cryo-electron microscopy (Cryo-EM), which is computer intensive.
“The structure looked correct and in line with results reported by other groups but the authors spotted small patches of unexpected ‘electron density’ embedded at the same place in each of the 3 components of each spike trimer. Comparing the shape of the density with all the structures in public databases revealed about 3 structures that had similar patches of density, caused by known molecules. This pointed to the linoleic acid, a polyunsaturated omega-6 fatty acid (found in plant oils) that is essential to our diet, required for formation of prostaglandins (involved in signalling and homeostasis) and in formation of cell membranes.
“As far as I am aware, this is the first time that a fatty acid has been found embedded in a virus glycoprotein inserted into its envelope (a lipid bag containing the genetic material of the virus). There is however a precedent from a totally different type of virus that also causes common colds, the rhinovirus. These have a particle (capsid) made of proteins assembled into a symmetrical, near-spherical, icosahedral particle (think geodesic domes like the Eden Project, children’s climbing frames or footballs), stabilised by a natural ‘fatty acid-like molecule’. In both of these different viruses, the role of the fatty acid seems to be to stabilise the protein or the particle before it interacts with receptors on the surface of the cell.
“Identification of the fatty acid in rhinovirus eventually led to a chemical mimic that acted as an antiviral, Pleconaril. In trials, it shortened the length of the cold by a day and it was licensed for emergency use against related more dangerous picornaviruses. However, it has side effects (for instance, reducing the effectiveness of the contraceptive pill) that precluded wider uptake.
“The linoleic acid-binding pocket in SARS-COV-2 will make an attractive target for possible designer drugs, lead candidates for which already exist from screens for rhinovirus. Drug development and testing is likely to take some time and might have limited effect, or might need to be taken shortly after infection. Unless the drugs are already well known and tested, there will also be a need to test well for possible side effects.
“The discovery, which is robustly supported by comprehensive study using several different approaches, might also offer insight into COVID-19 pathology, given the various functions of linoleic acid as an essential fatty acid.”
Prof Melanie Welham, Executive Chair of the Biotechnology and Biological Sciences Research Council (BBSRC), said:
“The Covid-19 pandemic has mobilised scientists all over the world to collaborate. Through curiosity-driven research we are discovering surprising things about this new virus. The fascinating findings from this study – in part made possible through work with BrisSynBio, a BBSRC / EPSRC funded Synthetic Biology Research Centre – could be vital as we seek ways to control and defeat the virus.”
‘Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein’ by Christine Toelzer et al. was be published in Science on Monday 21 September 2020.
DOI: 10.1126/science.abd3255
https://science.sciencemag.org/content/early/2020/09/18/science.abd3255
Declared interests
Prof Stephen Evans: “No conflicts of interest. I am funded (1 day/week) by LSHTM. They get funding from various companies, including Astra Zeneca and GSK but I am not funded by them, I have no involvement in obtaining funding from them and I am not an investigator or any grants obtained from them. I am the statistician to the “meta-Data Safety and Monitoring Board” for CEPI. I will probably be paid for my attendance at meetings and expenses for travel.”
None others received.