Solid- and solution-phase synthesis of heparin and other glycosaminoglycans

Abstract

Described is a modular, general synthetic strategy for the preparation in solution and on a solid support of heparin, heparin-like glycosaminoglycans, glycosaminoglycans and non-natural analogs of each of them. Additionally, the modular strategy provides the basis for the preparation of combinatorial libraries and parallel libraries of defined glycosaminoglycan oligosaccharides. The defined glycosaminoglycan structures may be used in high-throughput screening experiments to identify carbohydrate sequences that regulate a host of recognition and signal-transduction processes. The determination of specific sequences involved in receptor binding holds great promise for the development of molecular tools which will allow modulation of processes underlying viral entry, angiogenesis, kidney diseases and diseases of the central nervous system. Notably, the present invention enables the automated synthesis of glycosaminoglycans in much the same fashion that peptides and oligonucleotides are currently assembled.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of priority to the filing date of U.S. Provisional Patent Application Ser. No. 60 / 263,621, filed Jan. 23, 2001.BACKGROUND OF THE INVENTION [0002] Nucleic acids, proteins and polysaccharides constitute the three major classes of biopolymers. While the first two systems are principally linear assemblies, polysaccharides are structurally more complex. This structural and stereochemical diversity results in a rich content of “information” in relatively small molecules. Nature further “leverages” the structural versatility of polysaccharides by their covalent attachment (i.e., “conjugation”) to other biomolecules such as isoprenoids, fatty acids, neutral lipids, peptides or proteins. Oligosaccharides in the form of glycoconjugates mediate a variety of events including inflammation, immunological response, metastasis and fertilization. Cell surface carbohydrates act as biological markers for various tumors and as binding site...

AI Technical Summary

Benefits of technology

[0017] Described is a modular, general synthetic strategy for the preparation in solution and on a solid support of heparin, heparin-like glycosaminoglycans, glycosaminoglycans and non-natural analogs of each of them. Additionally, the modular strategy provides the basis for the preparation of combinatorial libraries and parallel libraries of defined glycosaminoglycan oligosaccharides. The defined glycosaminoglycan structures may be used in high-throughput screening experiments to identify carbohydrate s...

Problems solved by technology

While the first two systems are principally linear assemblies, polysaccharides are structurally more complex.

The heterogeneity of heparin results in many severe side effects, making this inexpensive drug dangerous and necessitates close monitoring.

156. With the exception of the AT-III-heparin interaction, the relationship between structure and function of HLGAGs is still poorly understood due to the complexity and heterogeneity of these poly

While many lectins have been purified and cloned, their ligands have not been identified due to the heterogeneous nature of carbohydrates.

Glycoconjugates are difficult to isolate in homogeneous form from living cells since they exist as microheterogeneous mixtures.

The purification of these compounds, when possible, is at best tedious and generally provides only very small amounts of the compounds.

However, the level of complexity associated with the synthesis of an oligosaccharide on a polymer support dwarfs that associated with the other two classes of repeating biooligomers.

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