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Sweetening Therapeutic Synthesis

Some 100,000 times a year, patients with sickle cell disease arrive at emergency rooms across the country wracked by excruciating pain. The cause: a logjam of platelets and rigid, misshapen, “sickled” red blood cells blocking circulation inside blood vessels. A number of these patients are treated and released, but about three quarters are admitted for an average stay of six days in the hospital, given powerful painkillers, intravenous fluids and sometimes blood transfusions.

These blockages actually begin with white blood cells that bind to vessel walls with the aid of selectins, a type of cell adhesion molecules. The reaction is much like a tennis ball running into a patch of Velcro, with a layer of carbohydrates making up the  “fuzz” on that “tennis ball,”  the white blood cells.

A new drug that targets this interaction between selectins and sugars is in Phase 2 clinical trials at multiple centers throughout the U.S. and Canada. The hope is that GMI-1070—a new orphan drug produced by GlycoMimetics in Gaithersburg, Maryland—will shorten the duration of these blockages and restore blood flow in humans, just as it did in earlier studies in mice. “There are currently no therapies that can interrupt the course of a vaso-occlusive crisis in sickle cell disease once the crisis is underway,” says Helen Thackray, the company’s vice president of drug development. If clinical trials prove successful, this fast-tracked drug could be available in four or five years.

GMI-1070 is just one promising compound produced as part of a growing effort to create next-generation, carbohydrate-based therapeutics. The complex carbohydrates, or glycans, that attach to and “sugarcoat” cells via proteins and lipids are crucial in many biological processes. Those include cell communication, cell identification, cancer progression, immune function and the ability of various pathogens to attach to and infect cells, to name just a few.

Stumbling Blocks with Synthesis

It wasn’t until 1964 that carbohydrates were discovered to be recognition molecules. Twenty years later, they were characterized as recognition sites for infection, and by 1990 they were found to play a role in inflammation and tumor metastasis. Over the next decade, various companies attempted to make drugs out of carbohydrates, sparking a number of spectacular failures. Carbohydrates presented real challenges as drug candidates: they required large, continuously infused doses because of low affinity for their intended targets and were rapidly metabolized. But there were also successes, including development of the anti-influenza drug Tamiflu.

In general, though, it was hard to move forward because scientists lacked the tools to decipher the complex, branching structures of carbohydrates and ways to synthesize these molecules reliably and in large quantities.

Then, in 2001, the National Institutes of Health–funded Consortium for Functional Glycomics was created, launching a collaborative effort to study carbohydrate-protein interactions and making the data openly available. Since then, over 100 human carbohydrate-binding proteins and their carbohydrate receptors have been identified.

Researchers at universities and biotech companies now use nuclear magnetic resonance, mass spectroscopy and supercomputers to elucidate the structure of glycans and their range of activities. It’s all part of the search for possible therapeutic targets for a variety of disorders from the still-nascent field of “glycobiology” drug development. So far, 14 carbohydrate-derived drugs are on the market.

“There are a lot of druggable targets,” says John Magnani, chief scientific officer of GlycoMimetics, “but in the past it’s been hard to translate a carbohydrate structure into a drug.” He notes that it has taken years to understand the unique challenges involved in producing carbohydrate-derived drugs. The company was formed in 2003.

Moving to Mimics

Now, biotech companies like GlycoMimetics are taking a different approach, designing new chemicals that mimic specific carbohydrate-mediated functions. “What we’re trying to do is make mimics of those natural sugars, making mimics of nature’s own structures—not using nature’s own structures,” says Magnani. They are elucidating the key functional parts of carbohydrate structures that interact with binding sites, and using that information to create molecules that are easily synthesized and more drug-like. That includes increasing activity, lengthening half-life in the bloodstream and maintaining low toxicity.

The quality that makes the company’s lead compound, GMI-1070, so attractive as a sickle cell treatment is its ability to disrupt the inflammatory process by inhibiting selectins’ ability to attract and trap white blood cells inside vessels. GMI-1070 also impacts cell trafficking, the movement of mobile cells throughout the body. Those combined characteristics also make it a promising compound for treating multiple myeloma and other blood cancers. In those conditions, cancer cells migrate in and out of bone marrow—and when inside, they may be shielded from chemotherapy. When those cells re-emerge, they can stage a cancer recurrence.

When GMI-1070 was administered in tandem with chemotherapy in animal studies conducted at Boston’s Dana-Farber Cancer Institute, there was a greater reduction in tumor burden and an improvement in survival, says Rachel King, chief executive officer of GlycoMimetics.

Beating Up Bacteria

Another drug candidate currently under pre-clinical investigation, GMI-1051, is an anti-infective that targets Pseudomonas aeruginosa. This bacterium, which poses great danger to burn victims and immuno-compromised patients, is the source of one tenth of hospital-acquired infections and frequently causes lung infections in cystic fibrosis patients. Like many pathogens, it has become resistant to numerous antibiotics. Robert J. Woods, a professor of biochemistry and molecular biology at the University of Georgia, Athens, and of chemistry at the National University of Ireland, Galway, says, “New therapies based on glycomimetics and carbohydrate-based vaccines present complementary strategies that help combat growing drug resistance to existing antiviral and antibiotic agents.”

Pseudomonas aeruginosa has two virulence factors that can make it quite deadly: it’s toxic to white blood cells that fight the infection, and it paralyzes the cilia that sweep mucous from the lungs. GMI-1051, which would be used in combination with antibiotics, diminishes that virulence to make antibiotics more effective.

In general, glycobiology—and glycomimetics—remain relatively untapped areas for drug development. This technology opens up a wide range of possible new targets. That’s important, says King, “because there are still a lot of unmet medical needs.”