A specific plasminogen activator inhibitor-1 antagonist derived from inactivated urokinase
文献类型：期刊论文
| 作者 | 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
 |
| 出版日期 | 2016-10-01 |
| 卷号 | 20期号:10页码:1851-1860 |
| ISSN号 | 1582-4934 |
| 关键词 | Pai-1 Urokinase variants Protein structure Fibrinolysis Antithrombotic agent |
| 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 |
| URI标识 | http://www.irgrid.ac.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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来源：中国科学院大学
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