Key Laboratory of Chemical Biology (Ministry of Education), Institute of Biochemical and Biotechnological Drugs, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong, PR China.
National Glycoengineering Research Center, Shandong University, Jinan 250012, Shandong, PR China.
Org Biomol Chem. 2022 Nov 2;20(42):8323-8330. doi: 10.1039/d2ob01221a.
A chemoenzymatic approach, mimicking the biosynthetic pathway of heparin and heparan sulfate (HS), has been well developed to prepare a series of structurally well-defined heparin oligosaccharides with excellent anticoagulant activity in good overall yields. The current chemoenzymatic synthesis typically begins with an unnatural glycosyl acceptor, -nitrophenyl glucuronide (GlcA-PNP), which is convenient for detection recovery and purification, although it affords heparin molecules with undesirable structure characteristics. Herein, we describe a facile chemoenzymatic strategy assisted by the specific cleavage of heparinase III for the highly efficient synthesis of an unmodified heparin heptasaccharide which demonstrated potent anticoagulant activity and commensurate pharmacokinetic profiles with fondaparinux. This successful generic strategy is applicable to the scalable synthesis of diverse HS/heparin molecules with completely natural structural features as promising therapeutic agents.
一种模拟肝素和硫酸乙酰肝素（HS）生物合成途径的化学酶法已被很好地开发出来，用于制备一系列结构明确的肝素低聚糖，这些低聚糖具有良好的整体收率和优异的抗凝活性。目前的化学酶法合成通常从一种非天然的糖基受体 - 对硝基苯葡萄糖醛酸苷（GlcA-PNP）开始，这有利于检测回收和纯化，尽管它赋予肝素分子不理想的结构特征。本文描述了一种在肝素酶 III 的特异性切割辅助下的简便化学酶法策略，用于高效合成未经修饰的肝素七糖，该七糖具有很强的抗凝活性，与磺达肝癸钠相当的药代动力学特征。这种成功的通用策略适用于具有完全天然结构特征的各种 HS/肝素分子的规模化合成，是有前途的治疗剂。
