Science.qxp_Layout 7 23/02/2021 13:44 Page 1
SCIENCE
Pride of Bristol
Professor Christiane Berger-Schaffitzel, biochemistry bod at the University of Bristol, shares the science behind her groundbreaking Covid-19 discovery, and recalls her surreal lab commute through the deserted city during the peak of the first wave
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n autumn 2020, a ‘druggable pocket’ in the SARS-CoV-2 spike protein, which could be used to stop the virus from infecting human cells, was discovered by an international team of scientists led by the University of Bristol. Their findings were deemed potentially game-changing in defeating the pandemic, as it was believed that small molecule anti-viral drugs could be developed to target the pocket they discovered, and eliminate Covid-19. The Berger-Schaffitzel lab’s Professor Christiane tells us what it was like. TBM: How has it been to work in this field on something so very urgent at a time that will go down in history? Professor Christiane Berger-Schaffitzel: The lockdown in March lead us to pivot our activities to Covid-19 research. We assembled a team of very experienced postgraduates who volunteered to use our tools to dissect the SARS-CoV-2 virus. All of us were key workers and part of UNCOVER, University of Bristol’s Covid-19 emergency research group led by Adam Finn from Bristol Medical School. My husband’s team initially produced spike protein for vaccine development and to establish serology testing. Spike is the protein on the surface of the SARSCoV-2 virus that mediates human cell infection. My team used cryo-electron microscopy to quality control the sample they produced, by determining its 3D structure. It was a unique experience. It felt surreal to walk to work through a deserted Clifton, meet the same few people in otherwise empty laboratories and return again at night through a ghost town. The work was extremely focused and intense. Some team members even spent the night in the laboratory occasionally. How did the breakthrough come to pass? When we analysed the atomic structure of the SARS-CoV-2 spike glycoprotein, we discovered a previously unknown pocket – a sort of molecular cave – within in the protein. To our surprise, inside of the pocket, we found a small molecule. It turned out that this small molecule was linoleic acid. With the help of Andrew Davidson, a renowned Bristol coronavirus expert, and his team, we could show that binding of linoleic acid to the spike protein blocks virus replication. Thus, unexpectedly, we discovered not only a druggable pocket in the SARS-CoV-2 spike protein, but also a potential drug, linoleic acid, in the pocket, which could be used as antiviral to protect us for infection by the virus.
40 THE BRISTOL MAGAZINE
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MARCH 2021
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No 196
Tell us more about druggable pockets... Similar pockets are found frequently in other proteins which are implicated in diseases. Blocking such a pocket with a drug, typically a small molecule, can inhibit the function of such proteins and provide a cure. In our study, the small molecule is linoleic acid – it binds to the pocket and distorts the spike protein, dialling down the infectivity of the virus. Our data suggests that linoleic acid could be already a drug that could be used as a potent antiviral to protect us from infection. In the future, based on our discovery, new drugs could be developed that bind even better to the pocket to suppress viral infectivity entirely and eliminate Covid-19.
The editor of Science asked us upon submission to also alert the World Health Organisation and immediately make our discovery publicly available What happens when a team discovers something valuable? Covid-19 has revolutionised how we publish research findings. We submitted our manuscript describing this work to Science, one of the leading and most respected journals for cutting-edge research. Usually, it takes several months until a manuscript is evaluated and, if deemed important enough, published and thus made available to the public. Now, in contrast, the editor of Science asked us upon submission to also alert the World Health Organisation and immediately make our discovery publicly available by uploading on a preprint server, accessible by everybody prior to peer-review. Today’s speed of research and information sharing is unprecedented. What is special about linoleic acid? Linoleic acid is a very special molecule. It is a fatty acid and part of vitamin F. Our body cannot synthesise linoleic acid, we need to take it up with our diet. Under normal circumstances we have enough of it in our bodies, but it was shown that patients who
