Method to Synthesize Heparan Sulfate Libraries for Drug Screening

University of Georgia Research Foundation
posted on 06/01/2010

UGA researchers have developed a parallel combinatorial technique that has produced over a dozen HS oligosaccharides and has the potential to create many more. This approach involves the creation of modular disaccharide building blocks that can be combined in numerous ways to produce a range of HS oligosaccharides.

The utility of the modular building blocks has been illustrated by the preparation of a library of 12 oligosaccharides, and importantly, a standard set of reaction conditions could be employed for the preparation of all target compounds. These structures were employed to probe structural features of HS for inhibition of the protease, BACE-1. The significant and complex variations in activity with structural changes observed in this study support the view that important functional information is embedded in HS sequences.

Suggested Uses

Pivotal method for supplying diverse libraries of HS oligosaccharides to biologists and medicinal chemists for evaluating structure-activity relationships and novel pharmacological agents

Advantages

I. Only know method to synthesize complicated HS oligosaccharides in an efficient and economic manner

II. Can synthesize HS oligosaccharides with significant structural diversity

III. Heparan sulfate oligosaccharides have been used for microarray formation for rapid screening

Innovation Details

Detailed Description

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. It is in this form that HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation and tumor metastasis. Heparan sulfate has been shown to serve as cellular receptor for a number of viruses including the respiratory syncytial virus.

Very little information is known about the ligand requirements for binding and mediating biological activities by HS. This difficulty results from a lack of technology for established structure-activity relationships, which in turn is due to the structural complexity of HS. These oligosaccharides are of interest as potential drugs, but they are extremely difficult to synthesize. Until the present discovery, only about 100 HS oligosaccharides had been reported in the literature.

File Number: 1509

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This innovation currently is not available for online licensing. Please contact Rachael Widener at University of Georgia Research Foundation for more information.

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