Recent advances in the discovery and development of factor XI/XIa inhibitors.
Recent advances in the discovery and development of factor XI/XIa inhibitors.
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DOI：
10.1002/med.21503
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发表时间：
2018-09
影响因子：
13.3
通讯作者：
Afosah DK
中科院分区：
文献类型：
--
作者：
Al-Horani RA;Afosah DK
XIa 因子 (FXIa) 是一种丝氨酸蛋白酶同二聚体，属于内在凝血途径。 FXIa 主要催化 IX 因子活化为 IXa 因子，随后在共同凝血途径中将 X 因子激活为 Xa 因子。越来越多的证据表明 FXIa 在血栓形成中发挥重要作用，但对止血的贡献相对有限。因此，针对XI/XIa因子系统的抑制剂已成为一种范式转换策略，以开发新一代抗凝剂来有效预防和/或治疗血栓栓塞性疾病，而不会产生危及生命的内出血风险。在过去十年中，已经发现或设计了多种 XI/XIa 因子蛋白抑制剂，包括多肽、活性位点拟肽抑制剂、变构抑制剂、抗体和适体。还引入了最终减少因子XI的肝脏生物合成的反义寡核苷酸。一项包括接受选择性初次单侧全膝关节置换术的患者在内的 II 期研究表明，特定的因子 XI 反义寡核苷酸可有效保护患者免受静脉血栓形成，且出血风险相对有限。初步研究结果还证明了 XI/XIa 因子抑制剂在败血症、李斯特菌病和动脉高血压中的潜力。本综述重点介绍了 XI/XIa 因子抑制剂的各种化学、生化和药理学方面，旨在推进其临床应用的开发。
Factor XIa (FXIa) is a serine protease homodimer that belongs to the intrinsic coagulation pathway. FXIa primarily catalyzes factor IX activation to factor IXa which subsequently activates factor X to factor Xa in the common coagulation pathway. Growing evidence suggests that FXIa plays an important role in thrombosis with a relatively limited contribution to hemostasis. Therefore, inhibitors targeting factor XI/XIa system have emerged as a paradigm-shifting strategy so as to develop a new generation of anticoagulants to effectively prevent and/or treat thromboembolic diseases without the life-threatening risk of internal bleeding. Several inhibitors of factor XI/XIa proteins have been discovered or designed over the last decade including polypeptides, active site peptidomimetic inhibitors, allosteric inhibitors, antibodies, and aptamers. Antisense oligonucleotides which ultimately reduce the hepatic biosynthesis of factor XI have also been introduced. A phase II study, which included patients undergoing elective primary unilateral total knee arthroplasty, revealed that a specific factor XI antisense oligonucleotide effectively protects patients against venous thrombosis with a relatively limited risk of bleeding. Initial findings have also demonstrated the potential of factor XI/XIa inhibitors in sepsis, listeriosis, and arterial hypertension. This review highlights various chemical, biochemical, and pharmacological aspects of factor XI/XIa inhibitors with the goal of advancing their development towards clinical use.
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影响因子：
4.8
作者：
Bajaj, Madhu S.;Ogueli, Godwin I.;Bajaj, S. Paul
通讯作者：
Bajaj, S. Paul
影响因子：
2.7
作者：
Bolton, Scott A.;Sutton, James C.;Seiler, Steven M.
通讯作者：
Seiler, Steven M.
影响因子：
6.6
作者：
Al-Horani RA;Desai UR
通讯作者：
Desai UR
DOI：
10.1056/nejmoa1405760
发表时间：
2015-01-15
期刊：
The New England journal of medicine
影响因子：
--
作者：
Büller HR;Bethune C;Bhanot S;Gailani D;Monia BP;Raskob GE;Segers A;Verhamme P;Weitz JI;FXI-ASO TKA Investigators
通讯作者：
FXI-ASO TKA Investigators
影响因子：
7.5
作者：
Berliner, JI;Rybicki, AC;Billett, HH
通讯作者：
Billett, HH