Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

Abstract

Low-molecular-weight heparins (LMWHs) are carbohydrate-based anticoagulants clinically used to treat thrombotic disorders, but impurities, structural heterogeneity or functional irreversibility can limit treatment options. We report a series of synthetic LMWHs prepared by cost-effective chemoenzymatic methods. The high activity of one defined synthetic LMWH against human factor Xa (FXa) was reversible in vitro and in vivo using protamine, demonstrating that synthetically accessible constructs can have a critical role in the next generation of LMWHs.

Role of Deacetylase Activity of N-Deacetylase/N-Sulfotransferase 1 in Forming N-Sulfated Domain in Heparan Sulfate

“…The substrate specificities of the biosynthetic enzymes ultimately dictate the structures of HS (3). Understanding the biosynthetic mechanism of HS is critically important for delineating the structure/function relationship of HS as well as for improving a chemoenzymatic approach to synthesize HS-based therapeutics (4,5).…”

Chemoenzymatic synthesis of heparan sulfate and heparin

“…Toward these goals, five different oligosaccharides were synthesized. 15 Among these were 6-mer ULMW heparin target compound, very similar to fondaparinux, as well as a 10-mer and 12-mer that were in the size range of LMWHs. Because of the size and structural complexity of LMWHs, a more efficient chemoenzymatic method was required.…”

“…47 These steps can be further repeated to form deca- (13) and dodecasaccharide (14) to introduce three and four repeats of IdoA2S-GlcNS disaccharides as described in a recent publication. 15 …”

“…The use of UDP-GlcNTFA provides a means to introduce a GlcNS at precisely the desired position within an oligosaccharide. This strategy is now used to synthesize structurally homogeneous ultra-low molecular weight heparins, low-molecular weight heparins 14,15 and heterogeneous heparin-like polysaccharides. 41,42 A novel strategy to utilize a series of unnatural sugar nucleotides to synthesize heparin-like oligosaccharide was recently proposed by Chen and coworkers.…”

“…[4][5][6][7][8][9][10][11][12][13] In recent years, a chemoenzymatic synthesis has emerged using glycosyltransferases, epimerase and sulfotransferases. 14,15 Compared to chemical synthesis, the chemoenzymatic approach offers shorter synthetic routes, excellent recovery yields, and utilizes a few common precursors for the preparation of diverse HS oligosaccharide structures. This article reviews the recent development in the chemoenzymatic synthesis method and its progress towards the synthesis of HS oligosaccharide targets having diverse sulfation patterns.…”