Game-changer
Druggable pocket in SARS-CoV-2 spike protein could stop virus
BRISTOL, U.K.—“COVID-19, caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), represents a global crisis. [The] key to SARS-CoV-2 therapeutic development is unraveling the mechanisms driving high infectivity, broad tissue tropism and severe pathology,” wrote an international team of researchers led by the University of Bristol in an article published in the journal Science. The team included experts from Bristol UNCOVER Group, Imophoron Ltd., the Max Planck Institute for Biomedical Research and Geneva Biotech Sàrl. The study was supported by the Elizabeth Blackwell Institute, Oracle high-performance cloud computing and Genscript.
SARS-CoV-2 is surrounded by multiple copies of a glycoprotein, known as the “spike protein,” that plays an essential role in viral infectivity. The spike binds to the human cell surface, allowing the virus to penetrate the cells and start replicating, causing widespread damage.
The researchers have discovered a druggable pocket in the SARS-CoV-2 spike protein that they believe could be used to stop the virus from infecting human cells. They say their findings are a potential “game-changer” in defeating the current pandemic, and that small-molecule antiviral drugs developed to target the pocket they discovered could help eliminate COVID-19.
The team—headed by Prof. Christiane Schaffitzel from Bristol’s School of Biochemistry and Prof. 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. Oracle high-performance cloud computing enabled the generation of a 3D structure of the SARS-CoV-2 spike protein to allow the researchers to peer deep inside the spike and identify its molecular composition.
During the research, the team located a small molecule, linoleic acid (LA), that was buried in a tailor-made pocket within the spike protein. LA, a free fatty acid, is indispensable for many cellular functions. While the human body cannot produce LA, it absorbs this essential molecule through diet. LA plays a vital role in inflammation and immune modulation, which are both key elements of COVID-19 disease progression, and is also needed to maintain cell membranes in the lungs to enable proper breathing.
According to Berger, “We were truly puzzled by our discovery and its implications. So 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.”
“Our findings provide a direct structural link between LA, COVID-19 pathology and the virus itself and suggest that both the LA-binding pocket within the S protein and the multi-nodal LA signaling axis, represent excellent therapeutic intervention points against SARS-CoV-2 infections,” the authors wrote in the Science paper.
“From other diseases, we know that tinkering with LA metabolic pathways can trigger systemic inflammation, acute respiratory distress syndrome and pneumonia,” Schaffitzel explained. “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.”
In rhinovirus, which causes the common cold, a similar pocket was used to develop potent small molecules that bound tightly to the pocket and distorted the structure of the rhinovirus, stopping its infectivity. When these small molecules were successfully used as antiviral drugs in human trials, they defeated rhinovirus in the clinic. Based on their data, the Bristol researchers are optimistic that a similar strategy can now be pursued to develop small-molecule antiviral drugs against SARS-CoV-2.
“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 antiviral drugs that keeps the virus at bay. Our discovery of a druggable pocket within the SARS-CoV-2 spike protein could lead to new antiviral drugs to shut down and eliminate the virus before it enters human cells, stopping it firmly in its tracks,” Schaffitzel concluded.
