Preparation of Low Molecular Weight Heparin from a Remodeled Bovine Intestinal Heparin

J Med Chem. 2021 Feb 25;64(4):2242-2253. doi: 10.1021/acs.jmedchem.0c02019. Epub 2021 Feb 15.

Abstract

Bovine intestinal heparins are structurally distinct from porcine intestinal heparins and exhibit lower specific anticoagulant activity (units/mg). The reduced content of N-sulfo, 3-O-sulfo glucosamine, the central and critical residue in heparin's antithrombin III binding site, is responsible for bovine intestinal heparin's reduced activity. Previous studies demonstrate that treatment of bovine intestinal heparin with 3-O-sulfotransferase in the presence of 3'-phosphoadenosine-5'-phosphosulfate afforded remodeled bovine heparin with an enhanced activity reaching the United States Pharmacopeia's requirements. Starting from this remodeled bovine intestinal heparin, we report the preparation of a bovine intestinal low molecular weight heparin having the same structural properties and anti-factor IIa and anti-factor Xa activities of Enoxaparin. Moreover, this bovine intestinal heparin-derived "Enoxaparin" showed comparable platelet factor-4 binding affinity, suggesting that it should exhibit similarly low levels of heparin induced thrombocytopeneia, HIT.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticoagulants / chemical synthesis
  • Anticoagulants / metabolism
  • Anticoagulants / pharmacology*
  • Antithrombin III / antagonists & inhibitors
  • Antithrombin III / metabolism
  • Carbohydrate Sequence
  • Cattle
  • Enoxaparin / chemical synthesis
  • Enoxaparin / metabolism
  • Enoxaparin / pharmacology*
  • Molecular Weight
  • Platelet Factor 4 / antagonists & inhibitors
  • Platelet Factor 4 / metabolism
  • Sulfotransferases / chemistry
  • Swine

Substances

  • Anticoagulants
  • Enoxaparin
  • Platelet Factor 4
  • Antithrombin III
  • Sulfotransferases