COVID-19 Research: University Of Bristol Led Study Discovers Free Fatty Acid Binding Pocket In SARS-CoV-2 Spike Protein That Could Halt Virus In Its Tracks
Source: COVID-19 Research Sep 22, 2020 4 years, 1 month, 3 weeks, 1 day, 8 hours, 27 minutes ago
COVID-19 Research: A study led by researchers from University of Bristol-UK that also involved scientist from Max Planck Institute-Germany, University of Heidelberg-Germany and Geneva Biotech Sàrl-Switzerland has discovered a druggable pocket in the SARS-CoV-2 Spike protein that could be used to stop the virus from infecting human cells.
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The stud findings are published in the peer reviewed journal: Science
https://science.sciencemag.org/content/early/2020/09/18/science.abd3255
The study findings are a potential 'game changer' in defeating the current pandemic and small molecule anti-viral drugs developed to target the pocket discovered could help eliminate COVID-19.
The SARS-CoV-2 coronavirus is decorated by multiple copies of a glycoprotein, known as the 'Spike protein', which plays an essential role in viral infectivity. Spike binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage.
The study team headed by Professor Dr Christiane Schaffitzel from Bristol's School of Biochemistry and Professor Dr Imre Berger from the Max Planck-Bristol Centre for Minimal Biology, utilized a powerful imaging technique, electron cryo-microscopy (cryo-EM), to analyse SARS-CoV-2 Spike at near atomic resolution.
Then enabled by Oracle high-performance cloud computing, a 3-D structure of SARS CoV-2 Spike protein was generated allowing the researchers to peer deep inside the Spike identifying its molecular composition.
Surprisingly, the study team's analysis revealed the presence of a small molecule, linoleic acid (LA), buried in a tailor-made pocket within the Spike protein.
Linoleic acid is a free fatty acid, which is indispensable for many cellular functions. The human body cannot produce linoleic acid. Instead, the body absorbs this essential molecule through diet.
Interestingly, linoleic acid plays a vital role in inflammation and immune modulation, which are both key elements of COVID-19 disease progression. LA is also needed to maintain cell membranes in the lungs so that we can breathe properly.
Dr Berger told Thailand Medical News, "The study team was truly puzzled by our discovery, and its implications. So here we have linoleic acid, a molecule which is at the center of those functions that go haywire in COVID-19 patients, with terrible consequences. And the virus that is causing all this chaos, according to our data, grabs and holds on to exactly this molecule basically disarming much of the body's defenses."
"Based on what we know from other diseases, tinkering with linoleic acid metabolic pathways can trigger systemic inflammation, acute respiratory distress syndrome and pneumonia. These pathologies are all observed in patients suffering from severe COVID-19. A recent study of COVID-19 patients showed markedly reduced linoleic acid levels in their sera," Dr Schaffitzel further explained.
Dr Berger further adds, "Our discovery provides the first direct link between linoleic acid, COV
ID-19 pathological manifestations and the virus itself. The question now is how to turn this new knowledge against the virus itself and defeat the pandemic."
Fortunately there is reason for optimism as in rhinovirus, a virus causing 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, defeating rhinovirus in the clinic.
The stud team, based on their data, is optimistic that a similar strategy can now be pursued to develop small molecule anti-viral drugs against SARS-CoV-2.
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Dr Schaffitzel added,"COVID-19 continues to cause widespread devastation and in the absence of a proven vaccine, it is vital that we also look at other ways to combat the disease. If we look at HIV, after 30 years of research what worked in the end is a cocktail of small molecule anti-viral drugs that keeps the virus at bay. Our discovery of a druggable pocket within the SARS-CoV-2 Spike protein could lead to new anti-viral drugs to shut down and eliminate the virus before it entered human cells, stopping it firmly in its tracks."
The study team concluded, “Our 2.85 Å cryo-EM structure of SARS-CoV-2 spike (S) glycoprotein reveals that the receptor binding domains (RBDs) tightly bind the essential free fatty acid (FFA) linoleic acid (LA) in three composite binding pockets. The pocket also appears to be present in the highly pathogenic coronaviruses SARS-CoV and MERS-CoV. LA binding stabilizes a locked S conformation giving rise to reduced ACE2 interaction in vitro
. Our structure directly links LA and S, setting the stage for intervention strategies targeting LA binding by SARS-CoV-2. The LA-binding pocket thus presents a promising target for future development of small molecule inhibitors that, for example, could irreversibly lock S in the closed conformation and interfere with receptor interactions.”
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