SARS-CoV-2 is the virus responsible for COVID-19 pandemic.  As of today, this highly pathogenic coronavirus has definitely established his power globally, leaving behind more than 670’000 deaths and almost 18 million of infected people.  While important clues have emerged on its mechanism of action, key aspects of its capacity to infect human cells as well as the viral structure itself are still under investigation.

Since the beginning of the pandemic, studies have shown that SARS-CoV-2 coronavirus takes advantage of the angiotensin-converting enzyme II (ACE2) to enter and invade human cells1 (see also article on my blog: COVID-19: treatments tested before vaccine development), the affinity of SARS-CoV-2 for its receptor being higher as compared to the related coronavirus SARS-CoV.  On its envelope, the virus possesses a so-called Spike S-glycoprotein that is the key binding to ACE2 and is the factor driving severe infectivity.  With the help of the host cell enzyme furin, expressed in diverse human cells (such as lung, liver or intestine cells), SARS-CoV-2 allows the cut of the S-protein receptor binding domain (RBD) on a particular site, enabling it to be activated and functional to allow its attachment to the ACE2 receptor and its fusion to the host cell membrane2.  Noticeably, this function is not present in the two others deadly coronaviruses SARS-CoV and MERS-CoV.  Inside the cell, the virus can easily replicate and trigger the cascade of events necessary to allow maturation of new viral particles and induces an inflammatory storm in the neighboring cellular environment that is characteristic to COVID-19 pathology.  The infection with SARS-CoV-2 virus can lead to severe lung inflammation, but is also marked by a strong vascular component due to inflammatory damage of the endothelial cells in the heart, the kidneys, and intestines.

The Spike trimer binds linoleic acid

A new study, led by scientists from Bristol, Heidelberg and Geneva resulted in the discovery of a direct link between the SARS-CoV-2 structure and the fatty acid linoleic acid3.  The team made a unique finding that will undoubtedly address some key aspects of the present COVID-19 crisis and potentially lead to new treatments.

The authors produced SARS-CoV-2 Spike protein and other COVID-19 antigens to support the local serology testing efforts in Bristol.  In the purpose of determining the structure of the Spike S-glycoprotein, the authors expressed this secreted trimer in a baculovirus expression platform, enabling recombinant multiprotein production4.  Subsequently, infected insect cells, used in this system, and cultured in cod liver oil nutrient supplement (also containing essential free fatty acids), were able to express the trimer SARS-CoV-2 Spike protein.  By applying a technique called cryogenic electron microscopy (or cryo-EM), which enables a near-atomic resolution, the scientific team discovered a novel, important feature in the structure of the highly purified SARS-CoV-2 virus Spike.  They observed a non-protein density within the SARS-CoV-2 virus receptor binding domains not reported for any other SARS-CoV-2 Spike before.  In fact, they found that the three RBDs of the Spike trimer tightly and specifically bind to three molecules of the essential free fatty acid linoleic acid, in hydrophobic pockets mostly shaped by phenylalanines and tyrosines amino acids to form a greasy tube, allowing the fatty acid to incorporate comfortably, fitting like a hand in a glove.  Based on their data, the authors propose that the Spike protein acts like a scavenger and sequesters linoleic acid, which represents one of the most important molecules regulating inflammation in our organism.  This mechanism appears to be conserved among the highly pathogenic coronaviruses that caused the previous SARS and MERS outbreaks.

In addition, the authors found other molecular features mediating SARS-CoV-2 to free fatty acid linoleic acid.  Among them, they discovered that, as opposed to the previously reported linoleic acid free `Apo` structure, their ‘Holo’ Spike structure adopts a condensed, more rigid structure, when it binds to linoleic acid.  In that state, the three RBDs of the trimer are brought together and locked down.  Both the Apo and the Holo Spike structure dynamically interchange between an open form where an RBD swings up to bind the cellular ACE2 receptor, and the closed form where the RBDs are inaccessible.  The open form is the infectious form, while the closed form is not infectious as ACE2 binding is prevented.  Linoleic acid binding pushes the Spike protein much more towards the closed conformation.  Without linoleic acid, the scientists found that the open conformation, driving the binding of Spike to ACE2, is mostly (70-80%) open.  With linoleic acid, this equilibrium shifts markedly reducing the presence of open and infectious form to only 30%.

Now let’s imagine a custom-designed “Super-Linoleic Acid” molecule which would bind extremely well to the pocket discovered by this team, to lock the Spike protein 100% in the closed conformation structure – the virus would not be infectious at all.

Why is linoleic acid so important?

Lipids, key players in cellular functions, are highly involved in the regulation of the replication cycle of viruses.  Previous studies showed that linoleic acid, a polyunsaturated omega-6 fatty acid essential for humans, only available through nutrients intake and found in vegetable oils such as soybean, flaxseed/linseed, olive and some nuts, actively participates in the regulation of inflammation, immune modulation, and membrane structure and flexibility, as well as surface tension in lungs5.  Interestingly, various studies showed that lack of linoleic acid is highly implicated in the pathogenicity of SARS-CoV-2 coronavirus.  Indeed, while COVID-19 patients showed continuous decrease of free fatty acids including linoleic acid in their sera6, exogenous supplementation of linoleic acid or arachidonic acid (which sits down the linoleic metabolic pathway) suppresses virus replication5In addition, the metabolism of linoleic acid to arachidonic acid seems to be in the center of the lipid remodeling and associated with human-pathogenic coronavirus propagation.  In fact, alterations of linoleic acid metabolic pathway were already observed in acute respiratory distress syndrome and severe pneumonia, which are both important aspects underlying COVID-19 pathology.

The discovery made by Toelzer and colleagues could also explain in part why diabetic patients may have aggravated and intensified inflammatory conditions and increased risks for adverse and fatal outcome, when they are infected with SARS-CoV-2 virus7.  Indeed, linoleic acid is also a key substrate of GRP40 receptor, which sits at the surface of pancreatic beta-cells and promotes insulin release from these cells8.  Moreover, it also plays a key role in other metabolic pathways such as gluconeogenesis9 or de novo glucose production from the liver, also via its GPR40 partner.  With lack of linoleic acid, patients encountering metabolic stress may worsen their symptoms in the context of COVID-19.

A powerful precedence: Antivirals exploiting a similar pocket defeat rhinovirus in the clinic

While working on their project, the authors realized that a powerful precedence exists exploiting a similar phenomenon to defeat a different virus in the clinicThe team of the structural virologist Michael Rossman, several years ago exploited a fatty acid binding pocket in rhinovirus, responsible for the common cold to develop potent small molecule antiviral successfully abolishing rhinovirus infectivity in clinical trials (Phase I-III)10.  “What made us realize that our discovery is a possible game changer is the work of Michael Rossmann.  He exploited a similar fatty acid binding pocket in rhinovirus and drugged it with a fatty acid mimic.  It locked down the rhinovirus in a conformation that could no longer bind its cellular receptor.  We are confident that we can apply the same concept to SARS-CoV-2”, says Prof.  Imre Berger, the founder and managing director of the Max-Planck-Bristol Center for Minimal Biology and leader of the study. 

Perspectives: A druggable pocket in SARS-CoV-2 Spike protein

The discovery of a linoleic acid binding pocket in SARS-CoV-2 adds an important perspective on potential small molecule antiviral interventions that could be applied to dial down SARS-CoV-2 infectivity in humans, by blocking virus attachment to its cellular receptor.  According to the authors, the binding of linoleic acid to the Spike protein causes the hydrophilic anchor to switch to the closed-form of the protein structure, making it a target for the development of small-molecule drugs, which could potentially lock the protein in the closed configuration irreversibly and inhibiting viral infection.  On a commercial level, small molecules in market contrast to vaccines or monoclonal antibodies, are affordable and can be distributed globally.

The present study is certainly one of the most creative and unexpected findings since the beginning of the present crisis and has a high potential to hopefully soon show concrete therapeutical applications to help defeat the global crisis.


  1. Li et al(2020).  Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues.  Infect Dis Poverty 9 (1):45.
  2. Hoffman et al(2020).  A multibasic cleavage site in the spike protein of SARS-CoV-2 is essential for infection of human lung cells.  Molecular Cell 78 (4):779-784.e5.
  3. Toelzer, Gupta, Sathish and Borucu et al(2020).  Unexpected free fatty acid binding pocket in the cryo-EM structure of SARS-CoV-2 spike protein.  BioRXiVThis article is a preprint and has not yet been certified by peer review.
  4. Gupta et al(2019).  MultiBac: Baculovirus-Mediated Multigene DNA Cargo Delivery in Insect and Mammalian Cells.  Viruses 11(3):198.
  5. Yan et al (2019).  Characterization of the Lipidomic Profile of Human Coronavirus-Infected Cells: Implications for Lipid Metabolism Remodeling Upon Coronavirus Replication.  Viruses 11(1):73
  6. Shen B et al(2020).  Proteomic and Metabolomic Characterization of COVID-19 Patient Sera.  Cell 9;182(1):59-72.e15.
  7. Zabetakis et al2002.  COVID-19: The Inflammation Link and the Role of Nutrition in Potential Mitigation.  Nutrients 12: 1466
  8. Itoh et al(2003).  Free fatty acids regulate insulin secretion from pancreatic beta cells through GPR40.  Nature 422(6928):173-6.
  9. Na Suh et al(2008).  Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes.  Am J Physiol Cell Physiol 295(6):C1518-27.
  10. Liu et al(2015).  Structure and inhibition of EV-D68, a virus that causes respiratory illness in children.  Science 347 (6217): 71-75

A special thank to Prof.  Imre Berger with whom I had a great discussion about this wonderful project and to my friend Ivan Lazarevic, who reads carefully my work before I publish it.

Take home message:

Since the beginning of the COVID-19 pandemic, diverse strategic approaches have been developed by scientists from all over the world in order to find optimal therapeutic interventions to treat COVID-19 pathology and alleviate the spread of the SARS-CoV-2 virus.  Among these, very recently, one particular approach could pave the way to develop new drugs blocking the so-called Spike protein responsible for the coronavirus entry into the human cells.  Indeed, a team composed of scientists from the Universities of Bristol, Heidelberg and Biotech companies established in Heidelberg and Geneva discovered that the Spike protein of SARS-CoV-2 coronavirus directly binds to the fatty acid essential for humans linoleic acid.  By this mean, the Spike protein changes its structure, becomes less capable of binding to its receptor ACE2, and therefore blocks the virus to invade the cells.  The results obtained by Tolzer and colleagues add an important hint on druggable interventions for the COVID-19 pandemic, such as antiviral small molecules mimicking linoleic acid and that could be applied to remove SARS-CoV-2 virus infectivity and pathogenicity within human cells and treat patients undergoing this crisis, especially those with increased metabolic risks.