Scientists found a‘game changer’ that could halt coronavirus in its tracks

Last Updated 25 September, 2020. Cellspect Co., Ltd.

A druggable pocket in the SARS-CoV-2 Spike protein that could be used to stop the virus from infecting human cells has been discovered by an international team of scientists led by the University of Bristol. [1] The researchers say their findings, published in the journal Science, are a potential 'game changer' in defeating the current pandemic and add that small molecule anti-viral drugs developed to target the pocket could help eliminate COVID-19.   

 

In this ground-breaking study, the team headed by Professor Christiane Schaffitzel from Bristol's School of Biochemistry and Professor Imre Berger from the Max Planck-Bristol Centre for Minimal Biology, used a powerful imaging technique, electron cryo-microscopy (cryo-EM), to analyze SARS-CoV-2 Spike at near atomic resolution. The researchers explain that the surface of SARS-CoV-2 is covered by multiple copies of the S glycoprotein, which plays an essential role in viral infectivity. The S protein binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage. 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. [2, 3]     

 

Unexpectedly, the research team's analysis revealed the presence of a small molecule, linoleic acid (LA), buried in a tailor-made pocket within the Spike protein. LA is a free fatty acid, which is indispensable for many cellular functions. The human body cannot produce LA. Instead, the body absorbs this essential molecule through diet. Intriguingly, LA also 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. [2, 3]     

 

One of the lead researchers, Professor Imre Berger, said: “Here we have LA, 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.” Other lead researcher Professor Christiane Schaffitzel explained: “From other diseases we know that tinkering with LA metabolic pathways can trigger systemic inflammation, acute respiratory distress syndrome (ARDS) and pneumonia. These pathologies are all observed in patients suffering from severe COVID-19. A recent study of patients with SARS-CoV-2 showed markedly reduced LA levels in their sera.” [2, 3]

 

The researchers say that with 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 and stopping its infectivity. These small molecules were successfully used as antiviral drugs in human trials and show promise for treating rhinovirus clinically. [2, 3]

 

In conclusion, 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. This structure directly links LA and S protein, 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 protein in the closed conformation and interfere with receptor interactions. [1, 4] This discovery provides the first direct link between LA, COVID-19 pathological manifestations and the virus itself and it will be very promising for defeating the COVID19 epidemic If this new discovery can be successfully transformed into applied technology.

 References:

  1.  Christine Toelzer et al. Sep 21, 2020. “Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein” Science. DOI: 10.1126/science.abd3255

  2.  Victoria Rees. Sep 22, 2020. “Researchers discover druggable pocket on SARS-CoV-2 Spike protein” Drug Target Review.

  3. Sep 21, 2020. “Discovery of a druggable pocket in the SARS-CoV-2 Spike protein could stop virus in its tracks” University of Bristol press release.

  4. Sep 22, 2020. “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” Medical News press release.

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