By CAPosts 18 January, 2021 - 05:30pm 60 views
Sugars are the most abundant biomolecules in the world. In fact, it is estimated that they represent 70% of the weight of all living matter on the planet. Among their many functions, glycans - sugar chains - are responsible for something that is often overlooked: communication between cells. Almost all biological structures - such as cell membranes and proteins - are covered with a layer of glycans. This outer layer is essential for infectious processes, in which a pathogen interacts directly with the surface of our cells. And SARS-CoV-2, the virus that causes covid-19, is no exception
Approximately 70% of the entire surface of the spike protein is coated with glycans, as shown by a study led by Rommie Amaro , from the University of California at San Diego. "Sugars escape what we can see under the microscope," explains Amaro. There are techniques, such as cryoelectronic microscopy, capable of "freezing" biomolecules in order to observe them . "But sugars are moving too fast to be seen with this technology," he adds. Therefore, the researchers decided to use computer simulations to reconstruct the glaze that covers the spike protein, and thus understand its role during infection.
In the case of SARS-CoV-2, sugars are twice as essential. First, because they stabilize the spike in a conformation that allows it to engage with the ACE2 receptors on our cells, the process that initiates infection . Amaro and his team show that, by removing some glycans from the surface, the spike protein is destabilized and, in addition, the binding with these receptors is weakened. "This is the first time that a sugar has been identified as part of the melting process," says Elisa Fadda, a researcher at the University of Maynooth, in Ireland, and co-author of the study. Likewise, this coating of sugars also helps camouflage the coronavirus from our immune system. "All of our cells are coated in sugars," explains Fadda. The coronavirus has developed a glaze indistinguishable from that of our own cells and manages to go unnoticed. “If the protein was swarming around 'naked', our immune system would immediately recognize it as a threat. Thanks to the glycans, the virus does not seem strange ”. These new images of the coronavirus spike protein are very different from what we are used to seeing. This image depicts the spicule protein in light blue, and its sugar coating in dark blue (see upper image).
The results of Amaro's team give clues about possible treatments for covid-19. The coating is different in the different parts of the spike protein. The upper part has 62% of its surface coated, leaving more space available for treatments with large molecules, such as monoclonal antibodies, than the lower part. Computer simulations also reveal that this "glaze" is less effective at shielding the protein from small molecules, which could easily access around 80% of the surface area. Discovering the most vulnerable parts of the spicule can help researchers find more effective drugs against covid.
The study of the glycans that coat the coronavirus is also essential for the development of vaccines. The Pfizer-BioNTech, Moderna and AstraZeneca vaccines use our own cellular machinery to create copies of the coronavirus spike protein and generate an immune response without us having to suffer from the disease. In recent months, techniques have been developed that make it possible to analyze the different sugars that surround this "decoy" protein generated by vaccines and compare them with the real SARS-CoV-2 spike. Despite the fact that in both cases it is our cells that manufacture one and the other protein, their glazes are slightly different, according to some preliminary studies . This causes vaccines to sometimes generate imperfect decoys that elicit a weaker immune response. "The differences are minimal, in no case so dramatic as to affect the effectiveness of vaccines," says Fadda. "The important thing is to understand them, study them and learn for the development of future vaccines," he adds. In fact, groups are already researching new vaccines designed to avoid these problems , and some are already in the last phase of clinical trials.
All of our cells are coated in sugars. The coronavirus has developed a glaze indistinguishable from that of our own cells and manages to go unnoticed
It is curious how, since the first cases were detected in Wuhan a little over a year ago, we have heard of proteins, RNA, DNA and even lipids - the components of the coronavirus envelope that we can destroy using soap and water . but nobody mentions the importance of sugars. "It's quite common," explains Carme Rovira, ICREA research professor at the University of Barcelona . "They are often forgotten, even when the cell and its components are drawn in textbooks." And it is true, the membranes that surround our cells are completely covered with sugars. In 1900, the Austrian biologist Karl Landsteiner discovered blood groups, and thanks to this in 1907 the first successful blood transfusion was performed. However, it took several decades to discover that our red blood cells are coated in chains of sugars characteristic of groups A, B, AB and O. “These glycans are like barcodes, our cells can read them to identify each other, and it also detects threats, such as pathogenic bacteria and viruses ”, explains Rovira. For this reason, receiving a transfusion from someone with a different blood group can cause adverse immune reactions.
The functioning of one of our best weapons against the flu, the antiviral Tamiflu (oseltamivir), is also related to the chemistry of sugars. Influenza viruses use a protein in their envelope, neuraminidase, to detect a sugar from the “glaze” of our cells - sialic acid - and enter our cells, promoting infection. "The chemical structure of Tamiflu is very similar to sialic acid, so it tricks the proteins of the influenza virus, blocks them and slows the progression of the disease," adds Rovira. A good understanding of the structure, position and behavior of sugars is key to designing effective vaccines and drugs, both for COVID-19 and other diseases. "Cancer cells, for example, have a very dense coating of sugars, including some that camouflage them from our immune system." Many researchers are looking for ways to destroy this shield, to unmask tumor cells and make them more susceptible to our immune cells.
Rovira also uses computational methods to understand the molecular mechanisms of enzymes that are responsible for "decorating" our cells with glycans - forming the glaze - and last November it received, together with researchers from the University of Leiden and the University of York, more than nine million euros from the European Research Council (ERC) to investigate them. Computer studies are essential, work on the spike protein glaze “would have been practically impossible ten years ago” - says Rovira. Amaro and Fadda's team required almost two months of simulations on one of the most powerful supercomputers in the world: Frontera, in Texas. They also used the facilities provided by PRACE, the European alliance for advanced computing - to which the National Center for Supercomputing belongs - which already at the end of March launched a call to finance research that would help mitigate the impact of the pandemic .
After For decades studying the genome and proteome, it is the turn of the “glyome” - the set of structures made up of sugars distributed throughout our cells . Due to their chemical structure, sugars can form much more varied chains than DNA or proteins. "But they are also much more complex structures, we still have a lot to discover in order to decipher all their functions," concludes Rovira.