Department of Chemistry & Chemical Biology, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, United States.
J Med Chem. 2021 Feb 25;64(4):2242-2253. doi: 10.1021/acs.jmedchem.0c02019. Epub 2021 Feb 15.
Bovine intestinal heparins are structurally distinct from porcine intestinal heparins and exhibit lower specific anticoagulant activity (units/mg). The reduced content of -sulfo, 3--sulfo glucosamine, the central and critical residue in heparin's antithrombin III binding site, is responsible for bovine intestinal heparin's reduced activity. Previous studies demonstrate that treatment of bovine intestinal heparin with 3--sulfotransferase in the presence of 3'-phosphoadenosine-5'-phosphosulfate afforded remodeled bovine heparin with an enhanced activity reaching the United States Pharmacopeia's requirements. Starting from this remodeled bovine intestinal heparin, we report the preparation of a bovine intestinal low molecular weight heparin having the same structural properties and anti-factor IIa and anti-factor Xa activities of Enoxaparin. Moreover, this bovine intestinal heparin-derived "Enoxaparin" showed comparable platelet factor-4 binding affinity, suggesting that it should exhibit similarly low levels of heparin induced thrombocytopeneia, HIT.
牛肠肝素在结构上与猪肠肝素不同，表现出较低的特定抗凝活性（单位/毫克）。肝素抗凝血酶 III 结合部位中关键的 3-O-磺基、6-O-磺基葡萄糖胺含量降低，是导致牛肠肝素活性降低的原因。先前的研究表明，在 3'-磷酸腺苷 5'-磷酸硫酸存在的情况下，用 3-O-磺基转移酶处理牛肠肝素，可得到活性增强的修饰牛肝素，达到美国药典的要求。基于这种修饰的牛肠肝素，我们报道了一种牛肠低分子量肝素的制备方法，其具有与依诺肝素相同的结构特性和抗因子 IIa 和抗因子 Xa 活性。此外，这种源自牛肠肝素的“依诺肝素”表现出相似的血小板因子 4 结合亲和力，表明它应该表现出类似的低水平肝素诱导的血小板减少症（HIT）。
