4.4 Article

De novo synthesis of a narrow size distribution low-molecular-weight heparin

Journal

GLYCOBIOLOGY
Volume 24, Issue 5, Pages 476-+

Publisher

OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cwu016

Keywords

chemoenzymatic synthesis; heparin; low-molecular-weight heparin; sulfotransferases and oligosaccharides

Funding

  1. National Institutes of Health [HL094463, U01 GM102137, HL096679, UO1 HL117659]
  2. Royal Thai Government
  3. National Institutes of Health Training Grant [T32-HL007149]

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Heparin, a commonly used anticoagulant drug, is a mixture of highly sulfated polysaccharides with various molecular weights (MWs). The unique sulfation pattern dictates the anticoagulant activity of heparin. Commercial heparins are categorized into three forms according to their average MW: unfractionated heparin (UFH, MWavg 14,000), low-MW heparin (LMWH, MWavg 3500-6500) and the synthetic pentasaccharide (fondaparinux, MW 1508.3). UFH is isolated from porcine intestine while LMWH is derived from UFH by various methods of depolymerization, which generate a wide range of oligosaccharide chain lengths. Different degradation methods result in structurally distinct LMWH products, displaying different pharmacological and pharmacokinetic properties. In this report, we utilized a chemoenzymatic method to synthesize LMWH with the emphasis on controlling the size distribution of the oligosaccharides. A tetrasaccharide primer and a controlled enzyme-based polymerization were employed to build a narrow size oligosaccharide backbone. The oligosaccharide backbones were further modified by a series of sulfation and epimerization steps in order to obtain a full anticoagulation activity. Determination of the anticoagulation activity in vitro and ex vivo indicated that the synthetic LMWH has higher potency than enoxaparin, a commercial LMWH drug in clinical usage.

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