Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming
Potent Cyclic Peptide Inhibitors of FXIIa Discovered by mRNA Display with Genetic Code Reprogramming
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DOI：
10.1021/acs.jmedchem.1c00651
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发表时间：
2021-05-28
影响因子：
7.3
通讯作者：
Payne, Richard J.
中科院分区：
文献类型：
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作者：
Ford, Daniel J.;Duggan, Nisharnthi M.;Payne, Richard J.
接触系统包括一系列丝氨酸蛋白酶，其分别通过凝血的内在途径和激肽释放酶-激肽系统介导促凝血和促炎活性。已证明抑制接触系统的引发剂因子XIIa（FXIIa）可在动物模型中产生血栓保护和抗炎作用，并可作为开发抗血栓药物的潜在安全靶点。在此，我们描述了使用随机非标准肽集成发现（RaPID）mRNA展示技术来鉴定一系列有效的和选择性的FXIIa环肽抑制剂。在体外对环肽进行了评价，三种先导化合物表现出显著的aPTT延长、凝血酶生成减少和缓激肽形成抑制。我们还描述了我们通过丙氨酸扫描、类似物生成以及通过计算机模拟方法来识别结合FXIIa的关键残基以预测我们的先导环肽抑制剂的结合模式的努力。
The contact system comprises a series of serine proteases that mediate procoagulant and proinflammatory activities via the intrinsic pathway of coagulation and the kallikrein-kinin system, respectively. Inhibition of Factor XIIa (FXIIa), an initiator of the contact system, has been demonstrated to lead to thrombo-protection and anti-inflammatory effects in animal models and serves as a potentially safer target for the development of antithrombotics. Herein, we describe the use of the Randomised Nonstandard Peptide Integrated Discovery (RaPID) mRNA display technology to identify a series of potent and selective cyclic peptide inhibitors of FXIIa. Cyclic peptides were evaluated in vitro, and three lead compounds exhibited significant prolongation of aPTT, a reduction in thrombin generation, and an inhibition of bradykinin formation. We also describe our efforts to identify the critical residues for binding FXIIa through alanine scanning, analogue generation, and via in silico methods to predict the binding mode of our lead cyclic peptide inhibitors.