Targeting PAI-1 in Cardiovascular Disease: Structural Insights Into PAI-1 Functionality and Inhibition.
Targeting PAI-1 in Cardiovascular Disease: Structural Insights Into PAI-1 Functionality and Inhibition.
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DOI：
10.3389/fcvm.2020.622473
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发表时间：
2020
影响因子：
3.6
通讯作者：
Declerck PJ
中科院分区：
文献类型：
--
作者：
Sillen M;Declerck PJ
纤溶酶原激活物抑制物-1(PAI-1)是组织型纤溶酶原激活物(TPA)和尿激酶型纤溶酶原激活物(UPA)的主要生理性抑制物，属于丝氨酸蛋白酶抑制物(Serpin)超家族成员。PAI-1除了在纤溶和伤口愈合中发挥重要作用外，还在多种急慢性病理生理过程中发挥关键作用，包括心血管疾病、组织纤维化、癌症和年龄相关疾病。在治疗广泛的PAI-1相关病理的前景中，许多努力都致力于开发PAI-1抑制剂。这些抑制剂，包括低分子分子、多肽、抗体和抗体片段，在各种动物疾病模型中的使用提供了充分的证据，证明了它们在体内的有益作用，并在临床试验中取得了进展。然而，这些抑制剂目前都没有被批准用于人类治疗，主要是由于选择性和毒性问题。此外，PAI-1的构象可塑性在蛇类中是独一无二的，这给PAI-1抑制剂的鉴定和开发带来了真正的挑战。这篇综述将提供对PAI-1功能及其调控的结构洞察的概述，并将重点介绍抑制PAI-1活性的不同方法。
Plasminogen activator inhibitor-1 (PAI-1), a member of the serine protease inhibitor (serpin) superfamily with antiprotease activity, is the main physiological inhibitor of tissue-type (tPA) and urokinase-type (uPA) plasminogen activators (PAs). Apart from being crucially involved in fibrinolysis and wound healing, PAI-1 plays a pivotal role in various acute and chronic pathophysiological processes, including cardiovascular disease, tissue fibrosis, cancer, and age-related diseases. In the prospect of treating the broad range of PAI-1-related pathologies, many efforts have been devoted to developing PAI-1 inhibitors. The use of these inhibitors, including low molecular weight molecules, peptides, antibodies, and antibody fragments, in various animal disease models has provided ample evidence of their beneficial effect in vivo and moved forward some of these inhibitors in clinical trials. However, none of these inhibitors is currently approved for therapeutic use in humans, mainly due to selectivity and toxicity issues. Furthermore, the conformational plasticity of PAI-1, which is unique among serpins, poses a real challenge in the identification and development of PAI-1 inhibitors. This review will provide an overview of the structural insights into PAI-1 functionality and modulation thereof and will highlight diverse approaches to inhibit PAI-1 activity.
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影响因子：
1.4
作者：
Abboud, Nesrine;Ghazouani, Lakhdar;Mahjoub, Touhami
通讯作者：
Mahjoub, Touhami
影响因子：
4.8
作者：
Bijnens, AP;Gils, A;Declerck, PJ
通讯作者：
Declerck, PJ
影响因子：
3.5
作者：
ANDREASEN, PA;RICCIO, A;DANO, K
通讯作者：
DANO, K
DOI：
10.1016/0268-9499(90)90391-v
发表时间：
1990-01-01
期刊：
FIBRINOLYSIS
影响因子：
--
作者：
BOOTH, NA;CROLL, A;BENNETT, B
通讯作者：
BENNETT, B
血浆和血小板中的纤溶酶原激活物抑制剂（PAI-1）
影响因子：
6.5
作者：
BOOTH, NA;SIMPSON, AJ;MACGREGOR, IR
通讯作者：
MACGREGOR, IR