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Enzymatic Synthesis of Heparin and Heparan Sulfate

Organization:Rensselaer Polytechnic Institute, NY, US
I.P. Brief:This method provides a simple approach to synthesize heparan sulfate with the potential to expand it for the enzymatic synthesis of heparin drug and other biologically active heparan sulfate in large scales. In addition, this system could serve as a model to better understand the regulation of the biosynthesis of heparan sulfate.
Summary of I.P.:Chemical synthesis has been the major route to obtain structurally defined heparin and Heparan Sulfate oligosaccharides. This synthesis is extremely difficult and expensive, and is incapable of generating most larger oligosaccharide structures. The heparan sulfate sulfotransferases used in this study were expressed in bacteria, making a large amount of enzymes readily obtainable at a significantly lower production cost. Additionally, production costs are decreased by more that 1000-fold by coupling a PAPS regeneration system with the enzymatic modifications. An added benefit of this new method is that, by selecting appropriate enzymatic modification steps, the biological activity of heparan sulfate can be varied, including those associated with binding to antithrombin, fibroblast growth facthor-1 and -2, and to herpes simplex virus envelope glycoprotein D.
Patent:U.S. Provisional Application 60/680,392
Keywords:Heparin, Heparan Sulfate, Anticoagulant, Enzymatic Synthesis
Primary Industry:Pharma & Biotech
Specific Market:Anticoagulant drug synthesis
Market Size:Currently, worldwide heparin sales are estimated to be more than $4 billion, with a 15% yearly growth rate. The annual global market for anticoagulant therapies is approximately $6 billion.
State of the Art:A similar technique has been discovered which synthesizes on the microgram scale, whereas our method has been demonstrated on the milligram scale in the laboratory, and is scalable for industrial synthesis.
Figures of Merit:Synthesis of anticoagulent drug and other polysaccharides at 1000-fold decrease in cost and on a larger scale than is currently available.
Tech.  Obstacles:Upscaling to industrial capacity.
Market Obstacles:Regulatory approval.
Patent Landscape:The competing techniques that have been discovered are: 1.Balagurunathan, K., Lech, M. Z., Beeler, D. L., Wu, Z. L., and Rosenberg, R. D. (2003) Nat.Biotechnol. 21, 1343-1346 2.Lindahl, U., Li, J., Kusche-Gullberg, M., Salmivirta, M., Alaranta, S.,Veromaa, T., Emies, J., Roberts, I., Taylor, C., Oreste, P., Zoppetti, G., Naggi, A., Torri, G., and Casu, B. (2005) J. Med. Chem. 48, 349-352
Publications:Enzymatically redesigning the biological activities of Heparan Sulfate. Jingua Chen, Fikri Y. Avci, Eva M. Munoz, Miao Chen, Lars C. Petersen, Robert J. Lindhardt, Jian Liu. Submitted to Journal of Biological Chemistry, April 2005.
Research Team:5 Members, >50 years.


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