A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection
A novel hirudin derivative inhibiting thrombin without bleeding for subcutaneous injection
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一种新型皮下注射不出血抑制凝血酶的水蛭素衍生物
DOI：
10.1160/th16-05-0416
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发表时间：
2016-12
影响因子：
6.7
通讯作者：
Mo Wei
中科院分区：
文献类型：
--
作者：
Zhao Bing;Zhang Yanling;Huang Yinong;Yu Jinchao;Li Yaran;Wang Qi;Ma Yixin;Song Hou Yan;Yu Min;Mo Wei
目前，抗凝剂可用于预防血栓形成。凝血酶是止血和血栓形成的效应酶。我们设计了一种直接凝血酶抑制肽(DTIP)，通过分子模拟和同源模拟，证明了DTIP的C端与外切酶I相互作用，N端与凝血酶活性部位相互作用。DTIP可干扰人、大鼠和小鼠血浆凝血酶介导的凝血(每组10只)，并阻断体外人全血凝血。皮下注射DTIP后，大鼠的aPTT、PT、TT和CT均呈剂量依赖性延长(n=10)。在大鼠远端尾部横断实验中，DTIP的抗血栓剂量引起的出血明显少于比伐卢定。此外，DTIP在0.5-1小时内达到血药浓度峰值，与达比卡特兰乙塞酯相比，在给药5天后没有引起出血增加。用小鼠致死性肺血栓栓塞法和FeCl3诱导的小鼠肠系膜小动脉血栓模型评价DTIP的抗血栓作用。DTIP(1.0 mg/kg，sc)可预防深静脉血栓形成，并将肺血栓栓塞症的存活率从30%提高到80%。活体显微镜观察显示，DTIP(1.0 mg/kg，sc)可减缓FeCl3损伤所致的肠系膜小动脉血栓形成。这些数据表明，DTIP是一种新型的抗血栓药物，可用于预防血栓形成，而不会增加出血风险。有关本文的补充材料，请访问www.thapsis-online.com。
Summary Currently, anticoagulants would be used to prevent thrombosis. Thrombin is an effector enzyme for haemostasis and thrombosis. We designed a direct thrombin inhibitor peptide (DTIP) using molecular simulation and homology modelling and demonstrated that the C-terminus of DTIP interacts with exosite I, and N-terminus with the activity site of thrombin, respectively. DTIP interfered with thrombin-mediated coagulation in human, rat and mouse plasma (n=10 per group) and blocked clotting in human whole blood in vitro. When administered subcutaneously, DTIP showed potent and dose-dependent extension of aPTT, PT, TT and CT in rats (n=10 per group). The antithrombotic dose of DTIP induced significantly less bleeding than bivalirudin determined by transecting distal tail assay in rats. Furthermore, DTIP reached peak blood concentration in 0.5–1 hour and did not cause increased bleeding after five days of dosing compared to dabigatran etexilate. The antithrombotic effect of DTIP was evaluated in mice using lethal pulmonary thromboembolism model and FeCl3-induced mesenteric arteriole thrombus model. DTIP (1.0 mg/kg, sc) prevented deep venous thrombosis and increased the survival rate associated with pulmonary thromboembolism from 30 % to 80 %. Intravital microscopy showed that DTIP (1.0 mg/kg, sc) decelerated mesenteric arteriole thrombosis caused by FeCl3 injury. These data establish that DTIP is a novel antithrombotic agent that could be used to prevent thrombosis without conferring an increased bleeding risk. Supplementary Material to this article is available at www.thrombosis-online.com.
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影响因子：
1.1
作者：
Yaoting Chang;Yu-Feng Hu;J. Liao;C. Chern;Yenn-Jiang Lin;S. Chang;Cheng-hsueh Wu;S. Sung;Kang-Ling Wang;T. Lu;T. Chao;L. Lo;L. Hsu;Chih‐Ping Chung;P. Chang;W. Hsu;C. Chiou;Shih‐Ann Chen
通讯作者：
Yaoting Chang;Yu-Feng Hu;J. Liao;C. Chern;Yenn-Jiang Lin;S. Chang;Cheng-hsueh Wu;S. Sung;Kang-Ling Wang;T. Lu;T. Chao;L. Lo;L. Hsu;Chih‐Ping Chung;P. Chang;W. Hsu;C. Chiou;Shih‐Ann Chen
凝血酶受体在乳腺癌侵袭性中的作用。
影响因子：
8.8
作者：
Henrikson, KP;Salazar, SL;Fenton, JW;Pentecost, BT
通讯作者：
Pentecost, BT
影响因子：
6.4
作者：
WOJTUKIEWICZ, MZ;TANG, DG;HONN, KV
通讯作者：
HONN, KV
DOI：
10.2147/btt.s3415
发表时间：
2008-09
期刊：
Biologics : targets & therapy
影响因子：
--
作者：
Petros S
通讯作者：
Petros S
DOI：
10.1177/1074248410395941
发表时间：
2012-03
影响因子：
2.6
作者：
P. J. O'Brien;L. Mureebe
通讯作者：
P. J. O'Brien;L. Mureebe