Design of an Ultralow Molecular Weight Heparin That Resists Heparanase Biodegradation

Heparanase,
an endo-β-d-glucuronidase produced by
a variety of cells and tissues, cleaves the glycosidic linkage between
glucuronic acid (GlcA) and a 3-O- or 6-O-sulfated glucosamine, typified
by the disaccharide −[GlcA-GlcNS3S6S]–, which is found
within the antithrombin-binding domain of heparan sulfate or heparin.
As such, all current forms of heparin are susceptible to degradation
by heparanase with neutralization of anticoagulant properties. Here,
we have designed a heparanase-resistant, ultralow molecular weight
heparin as
the structural analogue of fondaparinux that does not contain an internal
GlcA residue but otherwise displays potent anticoagulant activity.
This heparin oligosaccharide was synthesized following a chemoenzymatic
scheme and displays nanomolar anti-FXa activity yet is resistant to
heparanase digestion. Inhibition of thrombus formation was further
demonstrated after subcutaneous administration of this compound in
a murine model of venous thrombosis. Thrombus inhibition was comparable
to that observed for enoxaparin with a similar effect on bleeding
time.