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Heparin prepared synthetically could replace animal-derived drug


Researchers at Rensselaer Polytechnic Institute and University of North Carolina at Chapel Hill have discovered an alternative way to produce heparin, a drug commonly used to stop or prevent blood from clotting. The findings could enable the current supply of the drug – now extracted from animal tissue – to be replaced or supplemented by the synthetic version. The new process also can be applied as a tool for drug discovery, according to the researchers.

Heparin is a complex carbohydrate used to stop or prevent blood from clotting during medical procedures and treatments such as kidney dialysis, heart bypass surgery, stent implantation, indwelling catheters, knee and hip replacements, and deep vein thrombosis. The annual worldwide sales of heparin are estimated at $3 billion.

"We have synthetically prepared heparin in quantities large enough for use in human medical treatments by engineering recently discovered heparin biosynthetic enzymes," says Robert Linhardt, the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer Polytechnic Institute. "These discoveries will enable us to effectively replace a variable raw material – heparin derived from processed animal organs – with a synthetic material – synthetic heparin – and have the same therapeutic result."

Research in Linhardt’s group at the Center for Biotechnology and Interdisciplinary Studies at Rensselaer focuses on complex carbohydrates such as heparin. After determining the structure of these molecules, researchers study their biological activities to establish a structure-activity relationship that may reveal lead compounds for new drug development.

Researchers at MIT first prepared a synthetic heparin, but, in amounts of less than 1 microgram, it was insufficient to treat humans, says Linhardt. One human dose of heparin is approximately 100 milligrams.

Rensselaer and UNC-Chapel Hill researchers successfully synthesized hundreds of milligrams of heparin by developing a large-scale process involving engineered enzymes and co-factor recycling. The new, scaleable process can be applied to synthesize other heparin-based structures that regulate cell growth and may have applications in wound healing or cancer treatment, according to the researchers. The findings were reported Dec. 30, 2005, in the Journal of Biological Chemistry in a paper titled "Enzymatic redesigning of biological active heparan sulfate."

The process also can be applied in solid phase synthesis as a tool for screening lead compounds with heparin-like structures for drug discovery, according to the researchers. The findings were published Jan. 13, 2006, in Biochemical and Biophysical Research Communication in a paper titled "Enzymatic synthesis of heparin related polysaccharides on sensor chips: Rapid screening of heparin-protein interactions."

Linhardt collaborated on the interdisciplinary project with Jian Liu, assistant professor of medicinal chemistry at University of North Carolina at Chapel Hill. Graduate and post-doctoral students involved in the work include: Jinghua Chen (UNC-Chapel Hill), Eva Munoz (Rensselaer), Fikri Avci (Rensselaer), Ding Xu (UNC-Chapel Hill), Melissa Kemp (Rensselaer), and Miao Chen (UNC-Chapel Hill). The work was supported by the National Institutes of Health and the American Heart Association. Rensselaer and UNC-Chapel Hill have jointly filed a provisional patent on the process.

Linhardt said additional research will seek to scale the process another million-fold to make it commercially viable.

Tiffany Lohwater | EurekAlert!
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