COVID-19: Discovery of a druggable pocket in the SARS-CoV-2 spike protein
When husband-and-wife dynamic duo Professors Imre Berger (Max Planck-Bristol Centre for Minimal Biology) and Christiane Schaffitzel (School of Biochemistry) found themselves in lockdown in March 2020, unable to teach or run their normal workday at the University of Bristol, they did not hang up their lab coats. Instead (while complying with all necessary safety measures) they assembled a cohort of volunteers from their teams and set to work to do what they could to stop COVID-19 in its tracks, as part of the bigger Bristol University COVID-19 Emergency Research Group (UNCOVER).
With only their COVID-19 lab work to focus on, the progress made was unusually fast. In just a few short months they published a seminal peer-reviewed paper in the journal Science, one of the most renowned scientific periodicals worldwide, detailing their discovery of a potential ‘Achilles’ heel’ in SARS-CoV-2, the virus causing COVID-19, and how this weakness could help in the fight against the pandemic. While many teams were looking at the possibility of a vaccine, the Berger – Schaffitzel team focused on the structure of the virus itself, and what it could tell us about its rapid and invasive progression through the body. Their discovery could well lead to a prophylactic approach to stopping the spread of this and any similar virus, potentially forestalling future outbreaks.
SARS-CoV-2 is decorated by multiple copies of a glycoprotein, known as the ‘spike protein’, which plays an essential role in viral infectivity. The spike binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage. The team used electron cryo-microscopy (cryo-EM) to analyse the SARS-CoV-2 spike at near-atomic resolution and generated a 3D structure allowing them to peer deep inside the spike. In doing so they discovered a druggable pocket that could be used to stop the virus infecting human cells. Intriguingly, their analysis also revealed a molecule binding tightly in the pocket, linoleic acid (LA). Moreover, they could show a dramatic effect – the spike protein could no longer bind as tightly to human cells when LA occupied the pocket, indicating that LA-bound virus may be less infectious. Working with Andrew Davidson, a coronavirus specialist, they confirmed that the LA functions as an antiviral, stopping the SARS-CoV-2 virus from multiplying. Thus, the researchers had not only discovered a druggable pocket in the spike, but also a drug – LA.
LA is a well-studied molecule which plays crucial roles in cellular metabolism. LA is essential, it cannot be synthesised in our body, and we take it up with diet. LA is a key precursor from which our body makes many important metabolites to control, for example, immune reactions and inflammation. LA is also needed to maintain cell membranes in our lungs so that we can breathe properly.
It is known from other diseases that tinkering with LA metabolic pathways can trigger systemic inflammation, acute respiratory distress and pneumonia. These pathologies are all observed in patients suffering from severe COVID-19. It appears that the virus, by grabbing and holding on to LA, scavenges exactly the molecule, LA, we depend on to regain control, effectively disarming our body’s defences. Indeed, in patients suffering from COVID-19, the serum LA levels are markedly reduced.(1) If a patient with severe COVID-19 ends up on a ventilator, their intake of LA will be even lower, further aggravating their predicament. The team’s discovery provides the first direct link between LA, COVID-19 pathological manifestations, and the virus itself. Taken together, this makes it so important to develop possible treatment strategies based on LA.
The next step is looking at how to turn this new knowledge against the virus, and previous studies show reason to be optimistic. In rhinovirus, which causes the common cold, a similar pocket was exploited to develop potent small molecules that bound tightly to the pocket distorting the structure of the rhinovirus, stopping its infectivity. These small molecules were successfully used as anti-viral drugs in human trials and show promise for treating rhinovirus clinically. The Bristol team, based on their data, believes that a similar strategy can now be pursued to develop anti-viral drugs against SARS-CoV-2. In fact, because LA itself is already bound so tightly by the virus, the team believes LA could already be a powerful and immediately available first anti-viral drug before even better anti-virals arrive.
‘That time during the first lockdown in 2020 was unique. Terrible, in many ways, but also unique and an opportunity we will likely never have again.’
While news of vaccines is important and encouraging, their efficacy and longevity is still unknown. 2020 has shown us how fast a vaccine can be brought to market when the right circumstances present themselves, but even at speed it will have taken almost a year for the first rollout. It is important to continue looking at other ways to combat this virus. Ananti-viral treatment using this discovered pocket could shut down and eliminate the virus before it even enters human cells, stopping it firmly in its tracks. The authors found that this pocket is not only present in SARS-CoV-2, but also in SARS 1 and MERS, which caused the previous coronavirus outbreaks. So, if deadly coronavirus strains presented themself, chances are they would also have this ‘Achilles’ heel’, and an LA-based anti-viral treatment could therefore work against them just as well.
So, what has it been like to deal with this global crisis as a scientist at Bristol? Speaking about the rapid results of their research, Professor Berger said: ‘We were able to work at a faster pace because of lockdown, essentially. We didn’t manage our other projects, focusing minds and effort. Our team members and all the scientists we worked with had this unique sense of purpose and incredible dedication to do what they could to help defeat the crisis. It was a special time. We are very proud of them. Professor Adam Finn, of the Bristol Medical School, did a fantastic job organising the effort, and the resulting UNCOVER group really brought everyone together, University-wide. It was very exciting to have our Friday morning meetings, listening to clinicians, epidemiologists and scientists from all walks of life, and to watch our horizons broadening rapidly. It’s amazing to see what can be accomplished with such an interdisciplinary taskforce.’
With their return to teaching and a somewhat more ‘normal’ workload, the team will now require dedicated funding to enable them to realise their vision of a potent antiviral treatment targeting the ‘Achilles’ heel’ in SARS-CoV-2 they found. The ambition of the team is to bring their discovery to the clinic as fast as possible, and Bristol, with its outstanding clinical trial expertise, is an ideal place to set this in motion.
(1) Shen, B. et al. (2020) ‘Proteomic and metabolomic characterization of COVID-19 patient sera’, Cell, 182(1), p59-72.e15.