End-Site-Specific Conjugation of Enoxaparin and Tetradeoxycholic Acid Using Nonenzymatic Glycosylation for Oral Delivery

Heparin
and low molecular weight heparins (LMWHs) have been the drug of choice
for the treatment or the prevention of thromboembolic disease. Different
methods are employed to prepare the LMWHs that are clinically approved
for the market currently. In particular, enoxaparin, which has a reducing
sugar moiety at the end-site of polysaccharide, is prepared by alkaline
depolymerization. Focusing on this end-site-specific activity of LMWHs,
we conjugated the tetraoligomer of deoxycholic acid (TetraDOCA; TD)
at the end-site of enoxaparin via nonenzymatic glycosylation reaction.
The end-site-specific conjugation is important for polysaccharide
drug development because of the heterogeneity of polysaccharides.
This study also showed that orally active enoxaparin and tetraDOCA
conjugate (EnoxaTD) had therapeutic effect on deep vein thrombosis
(DVT) without bleeding in animal models. Considering the importance
of end-specific conjugation, these results suggest that EnoxaTD could
be a drug candidate for oral heparin development.