Finding a chink in the novel coronavirus' armor has been perhaps one of the greatest medical challenges of this century. An international team of researchers has found that the SARS-CoV-2 weakness could, in fact, lie within its strongest weapon— its spike protein. According to the study, the COVID-19 causing pathogen's spike protein has a "pocket" that can be targeted using small-molecule antiviral drugs.
The study led by the University of Bristol found that the virus's spike protein—which it uses to access cells—has a region with an essential molecule called linoleic acid (LA ) embedded into it, which can be drugged into submission, and potentially aid in defeating the pandemic itself.
"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 entered human cells, stopping it firmly in its tracks," said Prof. Imre Berger, lead author of the study, in a statement.
The Notorious Spike Protein
Spikes are protein structures found on the surface of the SARS-CoV-2 virus that enable the infection of human cells, especially lung cells. An enzyme known as ACE2 (Angiotensin-converting enzyme 2) is present in the cell membranes of cells in the heart, arteries, lungs, intestines and the kidneys.
The infection of the cells begins when the spike protein binds with ACE2 cell receptors. As the infection progresses, it aids in the catalysis that promotes the release of the SARS-CoV-2's genetic material into the cell. Replication and widespread damage follow.
In order to acquire a deeper look inside the spike and understand its molecular composition, used a cutting-edge imaging technique—electron cryo-microscopy (cryo-EM). Facilitated by Oracle high-performance cloud computing, they generated a 3D structure of the spike. However, the scientists made an unexpected discovery in the process.
A Tailor-made 'Pocket'
The analysis of the spike revealed that a small molecule— a fatty acid known as linoleic acid (LA)—was buried in a custom-made pocket within the structure. LA is a crucial necessity of several cellular processes. However, the human body cannot produce LA on its own and acquires it by absorption from the daily diet. Also, the fatty acid is vital in the maintenance of the cell membranes of the lung cells, thereby, enabling easy breathing.
Incidentally, LA plays a pivotal role in inflammation and modulation of the immune system, both of which are integral components in the progression of COVID-19. "We were truly puzzled by our discovery, and its implications," expressed Prof. Berger.
"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," he explained.
Link Between LA and Adverse Outcomes of COVID-19
Citing a recent study, Prof. Christiane Schaffitzel said that COVID-19 patients suffering from COVID-19 showed a marked reduction in the levels of LA in their sera. Prof. Schaffitzel added, "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."
Highlighting the importance of the finding, Prof. Berger stated their discovery is the first to establish a connection between LA, the pathological manifestation of COVD-19 and the coronavirus itself. "The question now is how to turn this new knowledge against the virus itself and defeat the pandemic," he quipped.
Hope for Developing Treatment
At a time when finding an effective therapeutic compound to tackle the disease is elusive, the finding by the researchers offers hope. In older experiments, scientists have been able to exploit a similar pocket in the common cold-causing rhinovirus. Small yet potent molecules were developed that could bind tightly to the pocket and deforming it; essentially ending its ability to infect. These molecules were transformed into effective anti-viral drugs that showed promise for clinical treatment of rhinovirus in clinical trials.
The research team believes that with their data, a similar mechanism can be devised and a small antiviral molecule to neutralize SARS-CoV-2 can be developed. Pointing hopefully to the strides made in the treatment of HIV, another deadly viral disease, Prof. Schaffitzel concluded, 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."
