Druggable pocket in SARS-CoV-2 Spike protein can help eliminate COVID-19

An international team of researchers, headed by the University of Bristol, has identified a druggable pocket in the SARS-CoV-2 Spike protein that could be utilized to prevent the virus from infecting human cells.

Druggable pocket in SARS-CoV-2 Spike protein can help eliminate COVID-19
Professor Imre Berger. Image Credit: University of Bristol.

According to the team, this latest discovery is a potential “game changer” in combating the ongoing pandemic, and adding the small molecule anti-viral drugs designed to target the newly discovered pocket can help eradicate the COVID-19 disease.

The study was recently published in the Science journal on September 21st, 2020,

SARS-CoV-2 is decked by numerous copies of a glycoprotein called the “Spike protein”, which plays a crucial role in viral infectivity. Spike attaches to the surface of human cells, enabling the virus to enter the cells and start its replicating process, thereby resulting in extensive damage.

In this breakthrough study, the researchers led by Professor Christiane Schaffitzel from the School of Biochemistry at the University of Bristol and Professor Imre Berger from the Max Planck-Bristol Centre for Minimal Biology, employed a robust imaging technique, called electron cryo-microscopy (cryo-EM), to examine the SARS-CoV-2 Spike at near atomic resolution.

A 3D structure of SARS CoV-2 Spike protein, facilitated by Oracle high-performance cloud computing, was produced that enabled the team to closely look inside the Spike and ultimately identify its molecular composition.

To the researchers’ amazement, their analysis showed the presence of a tiny molecule, linoleic acid (LA), hidden in a customized pocket inside the Spike protein. Being a free fatty acid, LA is essential for several cellular functions. LA cannot be produced by the human body; rather, the body absorbs this vital molecule through diet.

Interestingly, LA plays a crucial role in immune modulation and inflammation, which are both major elements of the progression of COVID-19 disease. LA is also required to regulate cell membranes in the lungs so that individuals can breathe properly.

We were truly puzzled by our discovery, and its implications. So here we have LA, a molecule which is at the centre 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 defences.”

Imre Berger, Professor, Max Planck-Bristol Centre for Minimal Biology

Professor Schaffitzel explained, “From other diseases we know that tinkering with LA 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 LA levels in their sera.”

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.”

Imre Berger, Professor, Max Planck-Bristol Centre for Minimal Biology

But there is a reason for hope. In rhinovirus, a virus that causes the common cold, an analogous pocket was manipulated to create powerful small molecules that attached firmly to the pocket, twisting the structure of the rhinovirus and halting its infectivity.

Such small molecules were effectively used as anti-viral drugs in human trials and hold potential for treating the rhinovirus clinically. Based on their information, the Bristol team is optimistic that an analogous method can now be followed to develop small molecule anti-viral drugs against the SARS-CoV-2 virus.

According to Professor Schaffitzel, “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.

Professor Schaffitzel further added, “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.”

Oracle for Research unites researchers and cloud computing to help bring about beneficial change for our planet and its people. SARS-CoV-2 and COVID-19 are causing global devastation, and research efforts to find vaccines and treatments cannot move quickly enough.

Alison Derbenwick Miller, Vice President, and Oracle for Research

Miller continued, “We are so pleased that Oracle's high-performance cloud infrastructure enabled Professors Berger and Schaffitzel to examine the molecular structures of the coronavirus spike protein and make this powerful and unexpected new discovery that could help curb the pandemic and save lives.”

Source:
Journal reference:

Toelzer, C., et al. (2020) Free fatty acid binding pocket in the locked structure of SARS-CoV-2 spike protein. Science. doi.org/10.1126/science.abd3255.

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