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SARS-CoV-2's Sugar Coating Isn't Sweet

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Jorge's career has journeyed through organic chemistry and radiochemistry, plant physiology, and cancer research.

Sugars

Sugars—not only the crystalline white powder that dives into your morning coffee but the whole family of them: the fructose in mangoes, the lactose in milk, the maltose in barley, the glycogen in your muscles, the deoxyribose in your DNA—have been shaping us since the onset of life on earth. At the forefront of our offensive to disclose nature's secrets—a disputed, disguised territory within the complexity of the natural world—now the sugars' raid has moved into the front line of the most pressing scientific endeavour of our generation: the conquest of SARS-CoV-2, the COVID-19 virus.

Sugars' intricate configuration yields surprising outcomes. Like the undeveloped embryos of diverse mammal species, sugars have striking structural similarities that pose a challenge to scientists. Just like similar embryos give rise to broadly distinct animals, subtle differences between the molecular skeletons of sugars produce dissimilar chemical and biological properties.

Lactose, for example, consists of the same type and number of atoms than at least twenty other known sugars, including sucrose, your table sugar: 12 carbons, 22 hydrogens and 11 oxygens (C12H22O11). Their only differences are in the arrangement and orientation of a few atoms. Like detaching an arm and replacing it with the hand palm facing out would render a body with the same parts but different capabilities, replacing sucrose for lactose, could turn sweetness into a muddy bellyache. The fact that sugars are composed of just three elements magnifies their structural complexity and makes their analysis with current technology a sour pickle. And so, historically, budding scientists have said no thank you and chosen sweeter projects.

But the sugars' central role in nature has made their study unavoidable. From sperm coating, that enables sexual reproduction across the whole animal kingdom to snail goo that enables profit across a whole line of shiny-looking-skin products, sugars are everywhere. Sugars are to proteins and other biological molecules what Watson was to Holmes—they provide support, stability and functionality. Sugars can attach to proteins in a process called glycosylation and endow proteins, then called glycoproteins, with new structural and functional capabilities; they also make up the skeleton of DNA and RNA and bestow fats with the faculty of forming membranes—essential life sacks. Thereupon, Glycomics was born—a scientific field that studies the activity of sugars in biological processes. Viral attacks are not an exemption.

Viruses

Viruses are ultra-small particles, a one-thousandth the width of a hair, made of biological molecules and that can only co-exist with living organisms. From bacteria to plants and animals no life is virus-free. Most viruses are benign, and some provide benefits to their host organisms. Like certain bacteriophages, residents of our gut that can destroy harmful bacteria in mucus membranes and are an important element of our natural immune system. A small number of viruses though can turn the world upside down.

And they do that with the aid of sugars.

All organisms have defence mechanisms to avoid infectious attacks by others, whether the invaders are as small as a virus or as large as a worm. In animals, the main defence is the immune system which works by recognizing substances called antigens on the surface of the invading agent. Antigens consist of proteins or glycoproteins foreign to the host, even if they are coming from individuals from the same species. One reason why blood donations might induce rejection reactions in the recipients. Proteins are an obvious immunological target because of their diversity and uniqueness. In humans they are assembled of 20 amino acids knitted in linear sequences, consequently, a small, 100-amino acids protein, can be made from more combinations of amino acid sequences than the number of atoms in the universe, making it unfeasible for a foreign protein to be mistaken by the host's immune system as one of his own. Here is where sugars jump into action.


Viruses' sugar coating, aren't sweet for scientists

Viruses' sugar coating, aren't sweet for scientists

COVID-19

Viral particles, known as virions, are built-up of a nucleic acid surrounded by a coat of protein called capsid that tightly surrounds and protects its genetic material, either DNA or RNA. In some viruses, like SARS-CoV-2, the capsid is enveloped by a lipid membrane embedded with proteins. An assembly that sets up the most iconic image of 2020: that spherical balloon planted with cactus-like growths, representations of the Spike, which is the protein in charge of docking to cells in the host for the virus to download its genetic material. Like a cargo space ship downloads astronauts and resources into the space station through a docking port, the Spike's docking port is the "receptor binding domain" or RBD, and more specifically, through a shorter chain of about a hundred amino acids within it called the "receptor binding motif" or RBM. Impairing the port would wreck the virus, a reason why the RBD and RBM are the targets of vaccines under development.

It would all be too easy for the immune system if the Spike was just a protein, a bare protein. Most of its amino acid sequence has no resemblance to anything that mammals produce, hence, it would be immediately recognized as foreign and taken care of by antibodies and effectors of the immune system. But the viral proteins are not alone, they are glycosylated, in other words, dressed with shielding sugars. In SARS-CoV-2 a sugar coat covers over 50% of the exposed proteins (nearly 100% in the HIV—an "evasion strong virus"), preventing access to it by antibodies and other agents. Sugars, however, come in a large diversity of structures and configurations. In viruses, they come as glycans: linear or branched chains of sugar molecules linked by chemical bonds (cellulose, for example, is a glycan). Viral glycans, however, just like alien proteins, could be identified as a threat by host receptors in the immune system to trigger defence responses, that is, if they are foreign to the host.

But viruses evolved a camouflage mechanism to avoid detection: they highjack the host's glycosylation machinery and drag it to manufacture the same glycans that coat key host proteins. They then, disguise themselves and their viral proteins in a cover of the host's sugars—like Edgar the Bug, the farmer-looking quasi-cockroach alien of the sequel Men in Black—and escape from immune effectors: a troop of cells that execute a direct response such as B-cells that secrete antibodies and killer T-cells.

The battlefield, though, is more complex than in movies. Viruses' camouflaging sugars serve also to engage with the host receptors in entry mechanisms. In SARS-CoV-2 infections, the host's docking port is ACE2, a cellular membrane protein that plays a role in the regulation of blood pressure and the cardiovascular system. Both, host defences and viral resistance have evolved belligerent mechanisms of defence—most based on the activity of glycosylated proteins. Mammals have developed glycoproteins that act as barriers to inhibit pathogen adhesion to cell receptors, but viruses learned to recognized those too.

Striving to find SARS-CoV-2 vulnerable points, scientists at the University of California in San Diego have found that the virus' sugar coat is not as static as a dense boreal forest. To enable docking between the RBD and ACE2 the sugar shield of the virus oscillates between the "closed" and the "open" state where only 11% of the protein surface is covered. While the virus can only dock to ACE2 in the open state, the shield opening represents a chance for host-antibodies to circumvent the sugar forest, bind the Spike and deactivate the virus. But there is a caveat: the oscillations happen in the time-scale of millionths of a second, meaning that to find attack opportunities, virus-neutralizing antibodies must be fast. Or numerous. Hence, eliciting a lofty titer of antibodies is a die-for goal of vaccine developers.

SARS-CoV-2 sugar coating, in the meantime, might not be bulletproof, as French scientists at the University of Nantes hypothesize. But it depends who the virus infects. Turns out that when SARS-CoV—the old SARS virus that holds similarities to the new coronavirus—gets its glycan shield in certain host cells, the viral sugar-chains are similar to those in A- and B- antigens in the blood. Thus, except for people of the AB blood subgroup, all others—A, B and O—are gifted with anti-B, or anti-A, or both classes of antibodies. A recent study involving 1,980 COVID-19 patients supports these views. The research, authored by 120 scientists from several countries, found that individuals with blood group O were at lower risk of serious illness putatively thanks to that extra help from their pre-existing antibodies to recognize the viral sugars, bind to the virus, and mark it for destruction by the immune system.

As efforts to impair SARS-CoV-2 infectivity by attacking its glycan cover have been unfruitful, scientists have turned attention to the virus entry point: ACE2. It appears that disrupting ACE2's glycosylation impairs viral entry into the cells as well as the production of virions—its viral progeny—and the escalation of the infection. Chances are that the observed inter-person variability in the susceptibility to the infection might be due to natural variations in the glycosylation pattern of ACE2; that is, the type and arrangement of the sugars covering it, a hypothesis that needs further investigation. Meanwhile, two drugs that alter the glycosylation profile of ACE2 have made headlines: chloroquine and hydroxychloroquine. At least in vitro, they show to inhibit SARS-CoV-2 infection, but much remains to be investigated to prove their safety and effectiveness in real flesh-and-bone people.

These discoveries demonstrate the importance of understanding glycosylation and sugar's complex structures for the prospects of the development of vaccines and effective treatments. Moreover, vaccine designs affect the glycosylation profile of the anti-viral antibodies themselves and their ability to activate effectors in the immune system capable of protecting against new infections—yet another opportunity that the understanding of glycosylation offers to conquer viral infections.

And winning the COVID-19 war.

This content is accurate and true to the best of the author’s knowledge and is not meant to substitute for formal and individualized advice from a qualified professional.