作为抗凝固剂的因子VIIa的异位抑制剂
M S Dennis1, C Eigenbrot, N J Skelton
1Department of Protein Engineering, Genentech, Inc., South San Francisco, California 94080, USA.
Nature
|April 13, 2000
概括
新的抗凝剂通过向组织因子-因子VIIa复合体,有效地阻止血液凝结. 这些可以通过全性机制抑制X因子的激活,这为抗凝剂的开发提供了一种新的方法.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 药理学 药理学 是一个学科.
背景情况:
- 组织因子-因子VIIa复合体是凝血级联的关键启动者.
- 开发针对该复合体的强效和选择性抗凝剂对于治疗血栓性疾病至关重要.
研究的目的:
- 鉴定和描述组织因子-因子VIIa复合物的新抑制剂.
- 阐明抑制的作用机制和结构基础.
主要方法:
- 体显示使用纯粹的类图书馆来选抑制剂.
- 生物化学测试以确定中位抑制度 (IC50) 和凝血抑制.
- 核磁共振 (NMR) 谱学和X射线晶体学用于结构分析.
主要成果:
- 确定了针对具有纳米分子IC50值的组织因子-因子VIIa复合物的强抑制剂.
- 已证明选择性抑制组织因子依赖的凝血和X因子激活.
- 阐明了一种非竞争性,全性抑制机制,涉及与活性部位不同的因子VIIa上的异位结合.
- 确定了一个代表性 (E-76) 的溶液结构及其与因子VIIa的复合物,揭示了与晶体结构的结构相似性.
结论:
- 针对因子VIIa上的异位体的抑制剂代表了抗凝剂开发的新框架.
- 已识别的通过一种全性"开关"机制起作用,调节因子VIIa的活性.
- 这些发现为设计参与凝血的血清蛋白酶抑制剂提供了新的策略.
相关概念视频
EDTA: Auxiliary Complexing Reagents
EDTA titrations are usually carried out in highly basic conditions, where the fully deprotonated form of EDTA, Y4−, actively complexes with the free metal ions in the solution. Several metal ions precipitate as hydrous oxide (hydroxides, oxides, or oxyhydroxides) under these conditions, lowering the concentration of free metal ions in the solution. For this reason, auxiliary complexing agents or ligands such as ammonia, tartrate, citrate, or triethanolamine are used in EDTA titrations to...
Masking and Demasking Agents
EDTA titrations may necessitate masking and demasking agents to temporarily protect a particular metal ion in a mixture from the EDTA reaction. These agents facilitate the sequential analysis of the metal ions by forming stable complexes with some—but not all—metal ions during certain steps.
There are many masking agents, such as cyanide, fluoride, triethanolamine, thiourea, and 2,3-bis(sulfanyl)propan-1-ol (formerly 2,3-dimercapto-1-propanol), with the masking agent chosen based on the metal...
There are many masking agents, such as cyanide, fluoride, triethanolamine, thiourea, and 2,3-bis(sulfanyl)propan-1-ol (formerly 2,3-dimercapto-1-propanol), with the masking agent chosen based on the metal...
Anticoagulant Drugs: Low-Molecular-Weight Heparins
Hemostasis is a crucial process that prevents excessive blood loss from damaged blood vessels. It involves various mechanisms such as vasoconstriction, platelet adhesion and activation, and fibrin formation. The importance of each mechanism depends on the type of vessel injury. In contrast, thrombosis is the abnormal formation of a blood clot within the blood vessels, leading to potential complications if the clot obstructs blood flow. Thrombosis can be caused by increased coagulability of the...
Anticoagulant Drugs: Vitamin K Antagonists and Direct Oral Anticoagulants
Oral anticoagulants are vital tools in preventing and treating blood clotting disorders. This diverse class of medications can be categorized as vitamin K antagonists, exemplified by warfarin, and direct thrombin inhibitors (DTIs), such as dabigatran, as well as factor Xa inhibitors, including rivaroxaban.
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
Warfarin, a prominent vitamin K antagonist family member, exerts its effect by inhibiting the enzyme VKORC1 (vitamin K epoxide reductase complex 1). By hindering this enzyme, warfarin...
Antiplatelet Drugs: Prostaglandin Synthesis, P2Y12 and Glycoprotein IIb/IIIa Inhibitors
Antiplatelet drugs emerge as frontline defenders against the insidious threat of thromboembolic diseases, where abnormal clots obstruct vital blood vessels. These drugs stand as bulwarks, inhibiting platelet aggregation and clot formation, thereby mitigating the risk of life-threatening conditions like myocardial infarction, coronary artery disease, and thrombotic strokes.
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
Prostaglandin synthesis inhibitors, exemplified by the widely known aspirin, wield their power by irreversibly acetylating...
Venous Thrombosis III: Interprofessional Care
Venous thrombosis requires effective prevention and treatment strategies to improve patient outcomes and reduce potential complications.Prevention StrategiesHealthcare providers must prioritize preventing venous thromboembolism (VTE) for all adult patients upon admission. Interventions depend on bleeding and thrombosis risk, medical history, current medications, diagnoses, planned procedures, and patient preferences. Patients on bed rest should change positions every two hours and, if not...


