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	A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase
	Gong, Lihu1,2; Proulle, Valerie3; Fang, Chao3; Hong, Zebin1; Lin, Zhonghui1; Liu, Min1,2; Xue, Guangpu1; Yuan, Cai1; Lin, Lin3; Furie, Barbara3
刊名	Journal of cellular and molecular medicine
	2016-10-01
卷号	20期号:10页码:1851-1860
关键词	Pai-1 Urokinase variants Protein structure Fibrinolysis Antithrombotic agent
ISSN号	1582-4934
DOI	10.1111/jcmm.12875
通讯作者	Huang, mingdong(mhuang@fjirsm.ac.cn)
英文摘要	Fibrinolysis is a process responsible for the dissolution of formed thrombi to re-establish blood flow after thrombus formation. plasminogen activator inhibitor-1 (pai-1) inhibits urokinase-type and tissue-type plasminogen activator (upa and tpa) and is the major negative regulator of fibrinolysis. inhibition of pai-1 activity prevents thrombosis and accelerates fibrinolysis. however, a specific antagonist of pai-1 is currently unavailable for therapeutic use. we screened a panel of upa variants with mutations at and near the active site to maximize their binding to pai-1 and identified a potent pai-1 antagonist, paitrap. paitrap is the serine protease domain of urokinase containing active-site mutation (s195a) and four additional mutations (g37br-r217l-c122a-n145q). paitrap inhibits human recombinant pai-1 with high potency (k-d = 0.15 nm) and high specificity. in vitro using human plasma, paitrap showed significant thrombolytic activity by inhibiting endogenous pai-1. in addition, paitrap inhibits both human and murine pai-1, allowing the evaluation in murine models. in vivo, using a laser-induced thrombosis mouse model in which thrombus formation and fibrinolysis are monitored by intravital microscopy, paitrap reduced fibrin generation and inhibited platelet accumulation following vascular injury. therefore, this work demonstrates the feasibility to generate pai-1 inhibitors using inactivated urokinase.
WOS关键词	GENE DEFICIENT MICE ; MONOCLONAL-ANTIBODIES ; PEPTIDE ; PAI-1 ; CONVERSION ; BINDING ; FIBRIN
WOS研究方向	Cell Biology ; Research & Experimental Medicine
WOS类目	Cell Biology ; Medicine, Research & Experimental
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000384438600006
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2375878
专题	中国科学院大学
通讯作者	Huang, Mingdong
作者单位	1.Chinese Acad Sci, Fujian Inst Res Struct Matter, State Key Lab Struct Chem & Danish, Chinese Ctr Proteases & Canc, Fuzhou, Fujian, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Harvard Med Sch, Div Hemostasis & Thrombosis, Beth Israel Deaconess Med Ctr, Boston, MA USA 4.Aarhus Univ, Dept Mol Biol & Genet, Aarhus C, Denmark
推荐引用方式 GB/T 7714	Gong, Lihu,Proulle, Valerie,Fang, Chao,et al. A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase[J]. Journal of cellular and molecular medicine,2016,20(10):1851-1860.
APA	Gong, Lihu.,Proulle, Valerie.,Fang, Chao.,Hong, Zebin.,Lin, Zhonghui.,...&Huang, Mingdong.(2016).A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase.Journal of cellular and molecular medicine,20(10),1851-1860.
MLA	Gong, Lihu,et al."A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase".Journal of cellular and molecular medicine 20.10(2016):1851-1860.

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