Druggable Pocket Discovered In SARS-CoV-2 Spike Protein Could Stop Coronavirus in Its Tracks

A druggable pocket in the SARS-CoV-2 spike protein that could be used to stop the novel coronavirus from infecting human cells could be a potential game changer in defeating the ongoing COVID-19 pandemic.

SARS-CoV-2 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. In a ground-breaking study by researchers at the University of Bristol (Bristol, UK) used a powerful imaging technique, electron cryo-microscopy (cryo-EM), to analyze SARS-CoV-2 Spike at near atomic resolution. Enabled by Oracle high-performance cloud computing, a 3D structure of the SARS CoV-2 spike protein was generated, allowing the researchers to peer deep inside the spike and identify its molecular composition.

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 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 to breathe properly. 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 and show promise for treating rhinovirus clinically. Based on their data, the research team is optimistic that a similar strategy can now be pursued to develop small molecule anti-viral drugs against SARS-CoV-2.

"Our discovery provides the first direct link between LA, COVID-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," said Professor Imre Berger from the Max Planck-Bristol Centre for Minimal Biology.

“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," added Professor Christiane Schaffitzel from Bristol’s School of Biochemistry who led the study.

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