Synthetic Oligosaccharides as Heparin-Mimetics Displaying Anticoagulant Properties

Abstract

Heparin and low molecular weight heparins are major clinical anticoagulants and the drugs of choice for the treatment of deep venous thrombosis. The discovery of an antithrombin binding domain in heparin focused interest on understanding the mechanism of heparin's antithrombotic/ anticoagulant activity. Various heparin-mimetic oligosaccharides have been prepared in an effort to replace polydisperse heparin and low molecular weight heparins with a structurally-defined anticoagulant. The goal of attaining a heparin-mimetic with no unwanted side-effects has also provided motivation for these efforts. This article reviews structure-activity relationship (SAR) of structurally-defined heparin-mimetic oligosaccharides.

Anticoagulant heparan sulfate: structural specificity and biosynthesis

“…Further, chemical synthesis of non-analog heparin and HS oligosaccharides, larger than hexasaccharides, is extremely difficult, if not impossible, based on currently available methods for carbohydrate synthesis. While a number of groups continue to pursue the synthesis of heparin (48)(49)(50), it is likely that chemical synthesis alone will be incapable of generating most larger oligosaccharide structures. The application of HS biosynthetic enzymes for generating large heparin and HS oligosaccharides with desired biological activities offers a promising alternative approach.…”

Stopping Bacterial Adhesion: A Novel Approach to Treating Infections

“…An alternative approach to blocking receptor binding would be to block binding sites using adhesin analogues; however, this is not attractive as theses inhibitors are likely to be large immunogenic peptides. The development of carbohydrate-based therapeutics, although not without major difficulties, has increasing potential as technologies for synthesis of short oligosaccharides are becoming available [69,70,71,72]. Examples of polysaccharide drugs include pentosan polysulphate to treat interstitial cystitis [73].…”

A surface plasmon resonance-based solution affinity assay for heparan sulfate-binding proteins

“…The important role of HS/heparin in mediating these diverse biological functions has made these molecules the focus of much research [9][10][11]. The potential for mimetics of heparin/HS in the treatment of diseases such as cancer and cardiovascular disease, has been recognized and is an area of much recent interest [12][13][14]. The evaluation of binding specificities and affinities of potential ligands forms a major component of such drug discovery research.…”