Sugary Camouflage on Coronavirus Offers Vaccine Clues

coronavirus sars-cov-2

In the fight against viruses and other pathogens, scientists are looking beyond genes and proteins to the complex sugars, or glycans, on cell surfaces.

Jordana Cepelewicz | NAUTILUS

In this model of the surface spike protein that the SARS-CoV-2 virus uses to infect human cells, the glycans look like a forest canopy atop the folded peptide inside. Researchers hope to use such models to pinpoint vulnerable regions of the protein (colored in red), as well as shielded regions that likely won’t be effective vaccine targets (black). Credit: doi: 10.1101/2020.04.07.030445

Cells are furry. That might come as a surprise, since textbook illustrations so often represent a cell as smooth—“something like a balloon full of water,” said Elisa Fadda, a computational chemist at Maynooth University in Ireland. “But that is absolutely not true.” In reality, the surface of a cell is adorned with a forest canopy of sugars, intricate and diverse clusters of carbohydrates that extend like branches and leaves from protein tree trunks. And because that canopy is the face that a cell shows to the world, these complex carbohydrates, or glycans, play a critical role in its encounters and interactions with other cells or molecules.

The prominence of glycans in biomedical research has been rising for some time, as researchers have explored how the sugars help to activate, regulate and direct the immune response. The study of glycans’ structure and function in human health and disease has already led to a better understanding of various pathogens and to novel therapies and vaccines. But the COVID-19 pandemic has brought greater urgency to the subject because many scientists believe that knowledge of glycans could prove essential for combating the SARS-CoV-2 virus. Several research teams have already published the first detailed models of the virus’s glycans—models that point to the pathogen’s potential vulnerabilities.

The Many Vital Uses of Sugars

There’s a reason why genomics and proteomics have leapt ahead of glycomics: The sheer complexity of sugars makes them more difficult to study. DNA, RNA and proteins are linear molecules built according to defined sets of rules, and scientists have the tools to sequence, analyze and manipulate them. But glycans are branching structures that assemble without a known template. The same site on two identical proteins might be occupied by very different glycans, for instance. Glycans also have exponentially more potential configurations than DNA or proteins: Three different nucleotides can make six distinct DNA sequences; three amino acids can make six unique peptides; three glycan building blocks can form more than a thousand structures. Glycans are flexible, wobbly and variable; intricate, dynamic and somewhat unpredictable. Their analysis demands greater technical expertise and more sophisticated equipment.

As a result, “the area of glycobiology has been more of a specialist subdiscipline,” said Max Crispin, a glycobiologist at the University of Southampton in England and one of the leaders of the SARS-CoV-2 work on glycans (part of which was published in early May 2020 in Science).

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