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Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

2014; Nature Portfolio; Volume: 10; Issue: 4 Linguagem: Inglês

10.1038/nchembio.1459

1552-4469

Yongmei Xu, Chao Cai, Kasemsiri Chandarajoti, Po-Hung Hsieh, Lingyun Li, Truong Quang Pham, Erica Sparkenbaugh, Juzheng Sheng, Nigel S. Key, Rafał Pawliński, Edward N. Harris, Robert J. Linhardt, Jian Liu,

Blood Coagulation and Thrombosis Mechanisms

Heparin analogs can serve as potent anticoagulants, but heterogeneous structures in some preparations and lack of antidote for others can complicate treatments. A chemoenzymatic method that prevents reversible epimerization now enables reversible application of defined constructs in cells and mice. 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.