Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins

Science. 2011 Oct 28;334(6055):498-501. doi: 10.1126/science.1207478.

Abstract

Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process. Here, we report 10- and 12-step chemoenzymatic syntheses of two structurally homogeneous ULMW heparins (MW = 1778.5 and 1816.5) in 45 and 37% overall yield, respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacokinetic properties to Arixtra, as demonstrated in a rabbit model. The chemoenzymatic approach is scalable and shows promise for a more efficient route to synthesize this important class of medicinal agent.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis*
  • Anticoagulants / chemistry
  • Anticoagulants / pharmacokinetics
  • Anticoagulants / pharmacology
  • Antithrombins / chemistry
  • Antithrombins / metabolism
  • Binding Sites
  • Chemical Phenomena
  • Fondaparinux
  • Glycosyltransferases / metabolism
  • Heparin, Low-Molecular-Weight / chemical synthesis*
  • Heparin, Low-Molecular-Weight / chemistry
  • Heparin, Low-Molecular-Weight / pharmacokinetics
  • Heparin, Low-Molecular-Weight / pharmacology
  • Molecular Structure
  • Molecular Weight
  • N-Acetylglucosaminyltransferases / metabolism
  • Oligosaccharides / chemistry
  • Polysaccharides / chemistry
  • Polysaccharides / pharmacokinetics
  • Polysaccharides / pharmacology
  • Rabbits
  • Racemases and Epimerases / metabolism
  • Spectrometry, Mass, Electrospray Ionization
  • Substrate Specificity
  • Sulfotransferases / metabolism

Substances

  • Anticoagulants
  • Antithrombins
  • Heparin, Low-Molecular-Weight
  • Oligosaccharides
  • Polysaccharides
  • Glycosyltransferases
  • N-Acetylglucosaminyltransferases
  • heparosan synthase
  • N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase
  • Sulfotransferases
  • Racemases and Epimerases
  • Fondaparinux