Department of Medicinal Chemistry, Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond, VA 23298, United States.
Biochem Biophys Res Commun. 2012 Jan 6;417(1):382-6. doi: 10.1016/j.bbrc.2011.11.122. Epub 2011 Dec 1.
Sulfated low molecular weight lignins (LMWLs), designed as oligomeric mimetics of low molecular weight heparins (LMWHs), have been found to bind in exosite II of thrombin. To assess whether sulfated LMWLs recognize other heparin-binding proteins, we studied their effect on serine proteases of the coagulation, inflammatory and digestive systems. Using chromogenic substrate hydrolysis assay, sulfated LMWLs were found to potently inhibit coagulation factor XIa and human leukocyte elastase, moderately inhibit cathepsin G and not inhibit coagulation factors VIIa, IXa, and XIIa, plasma kallikrein, activated protein C, trypsin, and chymotrypsin. Competition studies show that UFH competes with sulfated LMWLs for binding to factors Xa and XIa. These results further advance the concept of sulfated LMWLs as heparin mimics and will aid the design of anticoagulants based on their novel scaffold.
硫酸化低分子量木质素（LMWLs）被设计为低分子量肝素（LMWHs）的低聚模拟物，已被发现能与凝血酶的外位 II 结合。为了评估硫酸化 LMWLs 是否能识别其他肝素结合蛋白，我们研究了它们对凝血、炎症和消化系统丝氨酸蛋白酶的影响。通过显色底物水解测定法，发现硫酸化 LMWLs 能强烈抑制凝血因子 XIa 和人白细胞弹性蛋白酶，适度抑制组织蛋白酶 G，而不抑制凝血因子 VIIa、IXa 和 XIIa、血浆激肽释放酶、活化蛋白 C、胰蛋白酶和糜蛋白酶。竞争研究表明，肝素与硫酸化 LMWLs 竞争与因子 Xa 和 XIa 的结合。这些结果进一步推进了硫酸化 LMWLs 作为肝素模拟物的概念，并将有助于基于其新型支架设计抗凝剂。
