Production and functional characteristics of a novel hirudin variant with better anticoagulant activities than bivalirudin.

IF 5.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Peijuan Ge, Min Jin, Zimo Li, Licheng Zhu
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引用次数: 0

Abstract

Current antithrombotic therapies face dual constraints of bleeding complications and monitoring requirements. Although natural hirudin provides targeted thrombin inhibition, its clinical adoption is hindered by sourcing limitations. This study developed a recombinant hirudin variant HMg (rHMg) with enhanced anticoagulant activity through genetic engineering and established cost-effective large-scale production methods. The synthesised HMg gene was expressed in E. coli BL21 via a pET vector plasmid, followed by nickel-affinity purification. Systematic evaluations demonstrated rHMg's antithrombin activity of 9573 ATU/mg, dose-dependent prolongation of APTT/PT/TT. It has superior thrombin inhibition with the IC50 and Ki values were 2.8 and 0.323 nM respectively compared to FDA approved drug bivalirudin (p < 0.001). The high-yield prokaryotic expression of rHMg with enhanced anticoagulant efficacy provides a novel strategy for developing affordable antithrombotic drugs, showing significant potential for cardiovascular disease management.

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一种抗凝血活性优于比伐鲁定的水蛭素新变体的制备及其功能特征。
目前的抗血栓治疗面临出血并发症和监测要求的双重限制。虽然天然水蛭素提供靶向凝血酶抑制,其临床应用受到来源限制的阻碍。本研究通过基因工程技术开发出抗凝血活性增强的重组水蛭素变异HMg (rHMg),并建立了具有成本效益的规模化生产方法。将合成的HMg基因通过pET载体质粒在大肠杆菌BL21中表达,并进行镍亲和纯化。系统评价显示rHMg抗凝血酶活性为9573 ATU/mg, APTT/PT/TT呈剂量依赖性延长。与FDA批准的比伐芦定相比,其IC50和Ki值分别为2.8和0.323 nM,具有较好的凝血酶抑制作用
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来源期刊
CiteScore
10.30
自引率
10.70%
发文量
195
审稿时长
4-8 weeks
期刊介绍: Journal of Enzyme Inhibition and Medicinal Chemistry publishes open access research on enzyme inhibitors, inhibitory processes, and agonist/antagonist receptor interactions in the development of medicinal and anti-cancer agents. Journal of Enzyme Inhibition and Medicinal Chemistry aims to provide an international and interdisciplinary platform for the latest findings in enzyme inhibition research. The journal’s focus includes current developments in: Enzymology; Cell biology; Chemical biology; Microbiology; Physiology; Pharmacology leading to drug design; Molecular recognition processes; Distribution and metabolism of biologically active compounds.
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