dHG-5 与其寡糖组分抗 iXase 及抗凝抗血栓活性的相关性分析

	dHG-5 与其寡糖组分抗 iXase 及抗凝抗血栓活性的相关性分析; Correlation analysis of dHG-5 and its oligosaccharides in anti-iXase, anticoagulant and antithrombotic activities
	孙会芳
导师	赵金华
摘要	Basic studies have showed that intrinsic coagulation pathway is closely related to pathological thrombosis and may not be necessary for hemostasis. Theoretically, antithrombosis with low bleeding tendency could be performed by inhibiting intrinsic coagulation pathway. Currently, anticoagulant medicines targeting intrinsic coagulation pathway in developing include factor XIIa inhibitor factor XIa inhibitors and factor IXa. Intrinsic factor Xase (f.IXa-f.VIIIa complex, iXase), as the terminal enzyme and rate-limiting enzyme in intrinsic coagulation pathway, may be an ideal target for anticoagulants with low bleeding tendency. Fucosylated glycosaminoglycan (FG) from sea cucumber has strong anticoagulant activity, but also the side effects of activating factor XII and platelets. dHG-5 is a depolymerization product with weight-average molecular weight (Mw) of 5.2 kDa, which is obtained from FG by β-eliminating depolymerization method. Pharmacological and pharmacodynamic studies showed that it had strong anti-iXase activity, anticoagulation and antithrombotic activity, and without obvious activation on factor XII or platelets. Currently, dHG-5, as a new anticoagulant targeting a new target, selective iXase inhibitors, is in the preclinical phase. dHG-5 is a multicomponent drug composed of a series of oligosaccharides homologue, its main components including oligosaccharides oHG-5, 8, 11, 14, 17, 20, 23, 26 and 29. In this paper, the pharmacological characteristics and the correlation of dHG-5 and its oligosaccharide components were studied from these aspects: targets selectivity, anticoagulation in vitro, antithrombosis in vivo and bleeding risk. And the pharmacodynamics of dHG-5 also was preliminarily studied. The main findings were as follows: (1)Anti-iXase activity: The anti-iXase activities of dHG-5 and its oligosaccharides were analyzed by chromogenic substrate assay. The results showed that the IC50 and Ki of anti-iXase of dHG-5 were 14.0 nM and 0.560 μM, respectively. The anti-iXase potencies of dHG-5 containing oligosaccharides had a certain correlation with their molecular weight. Among them, the anti-iXase potency of oHG-5 was the weakest, and those of oHG-8 ~ 14 increased significantly with the increase of chain length, while the anti-iXase potencies between oHG-17 ~ 29 were approximate and close to the maximum potency. The relationship between the anti-iXase potencies (y) and Mw (x) of dHG-5 containing oligosaccharides could be approximately expressed as the power function: y = 1.66 × 1013 × x -3.25 (R2 = 0.997) in term of IC50 and y = 7.88 × 1011 × x -2.43 (R2 = 0.997) in term of Ki. The anti-iXase potency of oHG-5 was approximately equal to the weighted average sum of that of its oligosaccharide components (, [3n+2] represented the degree of polymerization of oligosaccharides，x represents the percentage of oligosaccharide in dHG-5, y was the anti-iXase potency of dHG-5 containing oligosaccharide ([IC50 or Ki of dHG-5] / [IC50 or Ki of dH
	2020-05
文献类型	学位论文
条目标识符	http://ir.kib.ac.cn/handle/151853/74175
专题	昆明植物所硕博研究生毕业学位论文
推荐引用方式 GB/T 7714	孙会芳. dHG-5 与其寡糖组分抗 iXase 及抗凝抗血栓活性的相关性分析, Correlation analysis of dHG-5 and its oligosaccharides in anti-iXase, anticoagulant and antithrombotic activities[D],2020.

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