Drug-affinity pocket found in novel coronavirus (SARS-CoV-2) echinocandins has potential to block virus transmission

An international team led by scientists from the University of Bristol has discovered a drug-affinity pocket in the SARS-CoV-2 spiny protein that could be used to prevent the virus from infecting human cells. The researchers say that their discovery, published today [21 September] in the journal Science, could be a "game-changer" in the fight against the current neo-crown virus epidemic. They also suggest that a small-molecule antiviral drug developed against the pocket-like structure they discovered may help eradicate COVID-19.

SARS-CoV-2 has multiple copies of a glycoprotein known as an "echinocandin," which plays a critical role in the virus' infectivity. The spines bind to the surface of human cells, allowing the virus to pass through the cell and begin replicating, causing widespread damage.

In this ground-breaking study, a team led by Professor Christiane Schaffitzel from the School of Biochemistry in Bristol and Professor Imre Berger from the Max Planck Centre for Microbiology in Bristol used powerful imaging techniques (electron cryomicroscopy cryo-EM) to analyse, with near-atomic resolution, the The SARS-CoV-2 echinoderm. The 3D structure of the SARS CoV-2 echinoderm protein was generated with the support of Oracle High Performance Cloud Computing, allowing the researchers to peer inside the echinoderm to identify its molecular composition.

Unexpectedly, the team's analysis revealed the presence of a small molecule, linoleic acid (LA), hidden in a specialized pocket of the echinoderm protein, a free fatty acid that is essential for many cellular functions. Instead of producing LA, the body absorbs this essential and important molecule through the diet. Notably, LA plays a critical role in inflammation and immune regulation, both of which are key elements in the development of COVID-19 disease. LA is also required to maintain the health of lung cell membranes so that we can breathe normally," said Professor Berger.

We were baffled by our discovery and what it implied," says Professor Berger. We've now discovered that LA is a central molecule for those functions that are dysregulated in COVID-19 patients with dire consequences. And according to our data, this virus that causes all of these disorders captures and retains precisely this molecule - that is, it basically disarms most of the body's defenses,"

Professor Schaffitzel explained: "We know from other diseases that altering LA metabolic pathways triggers systemic inflammation, acute respiratory distress syndrome and pneumonia. These symptoms have been observed in patients with severe COVID-19 disease. A recent study of COVID-19 patients showed a significant decrease in their serum LA levels."

Berger added, "Our findings provide, for the first time, a direct link between LA, the pathological manifestations of COVID-19, and the virus itself. The question now is how this new knowledge can be used against the virus to stop its epidemic."

There is reason to be hopeful about this. In rhinovirus, a virus that causes the common cold, effective small molecules have been developed using a similar pouch structure that distorts the structure of the rhinovirus by binding tightly to this pouch, thus ending its infectiousness. These small molecules have been successfully used as antiviral drugs in human trials to clinically defeat rhinoviruses. Based on these data, the Bristol team is optimistic that a similar strategy can now be adopted to develop a small molecule antiviral drug against SARS-CoV-2.

Professor Schaffitzel said: "COVID-19 continues to wreak havoc and wreak havoc on a massive scale, and until a proven vaccine emerges, it is vital to find other ways to fight the disease. If we look at the history of AIDS, after 30 years of research, what finally worked was a mixture of small-molecule antiviral drugs that stopped the virus in its tracks. The pocket of drug-affinity we found in the SARS-CoV-2 echinocandins has the potential to lead to the development of new antiviral drugs that could reliably stop the virus before it enters a human cell by inactivating it and destroying it."

Alison Derbenwick Miller, vice president of Oracle Research, added, "Oracle Research combines researchers with cloud computing to help bring about beneficial change for our planet and for people.The SARS-CoV-2 virus and the COVID-19 disease it causes have caused global devastation, and the search for the Research into vaccines and therapies cannot wait. We are delighted that Oracle's high-performance cloud infrastructure has enabled Professors Berger and Schaffitzel to examine the molecular structure of coronavirus echinocandins and make this powerful and unexpected new discovery to help curb pandemics and save lives."