September 23, 2020

Glycobiology gaining attention

“It is the Rodney Dangerfield of pharmaceutical research,” joked John Magnani of Maryland’s GlycoTech. “It gets no respect.” In fact, it did not even have a name until 1988, when Raymond Dwek of Oxford University coined the term “glycobiology” for the role carbohydrates play in biology and, more specifically, in human health.

The reason that carbohydrates have been largely ignored by biochemists is that they are hellishly hard to manipulate. They are formed from units of simple sugars strung together in chains that can twist and branch, giving them a number of three-dimensional shapes of which only one may have a desired biochemical activity. In nature, for example, two glucose polymers, starch and cellulose, are essentially identical but for the direction of a single bond hooking the glucose units together. Yet one is a major food source while the other is undigestible.

The problems of preparing carbohydrate compounds with just the right configuration are daunting, yet their role is so central to many human biochemical functions that they are increasingly gaining the attention of major pharmaceutical firms. Joseph Alper writes on the emerging field of glycobiology in the March 23 issue of Science.

Carbohydrates are found everywhere in the body, says Alper, and are intimately involved in health and disease. They combine with protein and fats to form glycoproteins and glycolipids and dot the surfaces of cells, often serving to identify them or act as a barometer as to the state of their health. They might convey the general message, “I’m human tissue, I belong here,” or something as specific as, “I’ve been injured, send help from the immune system over here.”

Alper says pathogens often use the glycoproteins or glycolipids identifying a cell as a beacon to home in on their tissue of choice when invading the body. Cancer cells often cloak themselves in carbohydrates to slip past immune cells, which take them for normal cells, as they migrate through the body. Drugs based on carbohydrates are being designed to thwart these actions, and there already have been some successes.

A little over a decade ago, a bacterium called Hib caused bacterial meningitis in 25,000 children each year with a fatality rate of 10 percent. Now, thanks to a sugar-based vaccine, Hib has been all but eliminated as a threat in the United States and Europe. But it was not an easily won victory, writes Alper, as 60 years elapsed between the discovery of the sugar groups on Hib that elicits an immune response and the development of an effective vaccine.

A much quicker result was obtained through a chance observation by Hudson Freeze of the Burnham Institute in LaJolla, Calif. While working with cells from slime molds deficient in the sugar mannose, Freeze noticed they were very similar in appearance to those from children afflicted with a congenital disorder known as CDG1b. This causes severe chronic gastrointestinal problems including diarrhea and bleeding. Freeze was able to normalize both types of cell by the addition of mannose. Shortly after publishing his observation, Freeze got a call from a German doctor who had a patient dying from CDG1b – a young boy bleeding so badly that he had already received 20 liters of blood! Freeze told him how much, and how often, to give the boy mannose. Six months later the doctor called back to say the boy was cured.

Other carbohydrate remedies being developed include a molecule by Synsorb Biotech of Calgary, Alberta, to combat severe diarrhea caused by bacterial toxins. It looks like a child’s toy ball, according David Cox, the company’s CEO, with a solid core and thousands of sugar strands dangling from it. The toxins have a strong affinity for the sugar strands, so the hope is that the “ball” will sweep the toxins from the body.

The Sloan-Kettering Cancer Center is testing a tumor vaccine with results expected within a year, and United Therapeutics of Maryland has successfully tested a drug for hepatitis B in woodchucks that exhibits none of the toxic effects of the standard treatment.

But one of the most exciting breakthroughs has to do with prions, small bits of protein, that cause such diseases as scrapie, mad cow disease and Creutzfeldt-Jakob disease (CJD) in humans. Studies have shown that differences among prions are due to the number, and type of, carbohydrates attached to the protein strand. There are two forms of CJD, “classical” that can be traced to a genetic disorder and “variant” (vCJD) whose cause was unknown until fairly recently. Researchers found that the carbohydrates attached to prions in vCJD are identical to those found in mad cow disease showing that vCJD is a human form of mad cow disease. Some day it may be possible to produce vaccines for these prion-based diseases by attacking the carbohydrates attached to them.

Clair Wood taught chemistry and physics at Eastern Maine Technical College for more than 10 years.

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