Chemoenzymatic Synthesis Of The Next Generation of Ultralow MW Heparin Therapeutics

Abstract

Heparin, a sulfated glycosaminoglycan, is a widely used injectable anticoagulant. This polysaccharide is a natural product extracted from porcine intestinal tissue. A specific pentasaccharide sequence is responsible for heparin’s high affinity towards anti-thrombin III, which undergoes a conformational change and, as a result, inhibits the blood coagulation Factor Xa, a critical serine protease at the convergence on the intrinsic and extrinsic activation pathway of the coagulation cascade. Due to its structural complexity and heterogeneity, the synthesis of the anti-thrombin III-binding sequence of heparin has been limited to a few approaches. The heparin contamination crisis in 2007 has motivated the development of alternative methods for the efficient preparation of safe heparin products. In this article, we discuss the current methods and recent advances in heparin and low MW heparin syntheses and the recent successful chemoenzymatic preparation of ultralow MW heparins.

Heparin–Polynitroxide Derivatives: A Platform for New Diagnostic and Therapeutic Agents in Cardiovascular Disease?

“…n To use synthetic heparinomimetics or specific glycosaminoglycans A promising approach is to use heparinomimetics such as sulfated derivatives of chitosan or semi-synthetic glycosaminoglycans [10,20]. Such polymeres may be targeted to the specific extracellular structures, which are distinct from the heparin-binding sites in the vascular wall.…”

“…In keeping with this strategy, we have recently synthesized novel heparin-polynitroxide (HPN) HPNs n Why heparin? Heparin is a highly sulfated glycosamino glycan composed of repeating disaccharide units of a-l-idoor b-d-glucopyranosiduronic acids which are linked to N-sulfo-d-glucosamine [9,10]. In addition to being widely used as an anticoagulant, heparin is known to have a high affinity for the variety of vascular extracellular structures and has been used as a carrier for the targeted delivery of stem cells and drugs.…”

Legislação Brasileira Aplicada À Produção Do Insumo Farmacêutico Ativo Heparina

“…Para exercer a sua função anticoagulante, a mesma requer um co-fator plasmático, a antitrombina III. A heparina fixa-se à antitrombina III, induzindo uma modificação conformacional dessa molécula, que expõe o sítio ativo acessível à trombina e às outras proteases resultantes da ativação dos fatores da coagulação (DELUCIA et al, 2007;MELLO et al, 2008;MASUKO;LINHARDT, 2012;MULLOY et al, 2016).…”

Preparation and application of a ‘clickable’ acceptor for enzymatic synthesis of heparin oligosaccharides

“…12,13 Employing a chemoenzymatic approach in our previous work, we successfully synthesized the ULMW heparin heptasaccharides with 10 and 12 steps in 45% and 37% overall yields based on the disaccharide acceptor degraded from heparosan (Figure 1), which showed very similar binding affinities and in vitro anti-Xa activities comparing with the commercial drug Arixtra. 14,15 …”