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Nov/Dec 2000
Vol. 3, No. 9, p. 20.

news in brief

Heparin syntheses

structure of heparin

Heparin constituents.

Heparin is a highly sulfated polysaccharide composed of glucuronic and iduronic acids linked to glucosamine residues.

During the past 20 years, researchers have developed automated and efficient methods of synthesizing proteins and oligonucleotides, but an efficient method of stringing together sugar residues has yet to be found.

The challenge has become more compelling as evidence mounts that carbohydrates play an important role in many normal and pathological biological pathways. A good example is the heparins. “There are quite a few proteins known to interact with heparins, and they are required for activation or inhibition of the protein,” says Geert-Jan Boons of the University of Georgia’s Complex Carbohydrate Research Center (Athens). Heparins contain sulfate groups that are believed to interact with proteins by forming disulfide linkages.

To understand the biological roles of heparins, researchers would like to synthesize various derivatives, but carbohydrates are difficult molecules to build. Each sugar building block has more than one reactive center, and the link between adjacent sugar residues can be either perpendicular or parallel to the plane of the carbon ring. “In my mind, it is nature’s way of doing combinatorial chemistry,” says Boons.

Boons and his team took a modular approach to the synthesis of heparins. They have so far identified 19 different disaccharide building blocks and have developed syntheses of the 6 most common ones. Boons estimates that this should allow them to construct 90% of naturally occurring heparins. The results were presented at the fall 2000 ACS national meeting in Washington, DC. And that’s important, because the Human Genome Project is turning up more and more proteins whose sequences suggest a connection to heparins—and that means plenty of potential targets for heparin derivatives or drugs that mimic them.

“There is an expectation that there are at least 500 proteins that will require heparin,” says Boons. In the next 5–10 years, there will be a whole host of proteins uncovered that require heparins, and we will require methodologies to identify motifs that govern these interactions, he says.


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