Cerastokunin 的结构、生化特征和分子机制:一种具有潜在凝血酶、Xa 因子和血小板抑制作用的新型 Kunitz 型多肽。

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Noussaiba Saghour, Fatah Chérifi, Samah Saoud, Younes Zebbiche, Amel Meribai, Nadjia Bekkari, Taright-Mahi Samya, Fatima Laraba-Djebari
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引用次数: 0

摘要

目前的研究重点是分离 Cerastes cerastes 毒液,以产生首个 Kunitz 型多肽。Cerastokunin 是一种 7.75 kDa 的多肽,根据其抗胰蛋白酶作用,通过三步层析将其纯化至均一。通过 LC-MALDI-MSMS 重新测序,发现 Cerastokunin 包含 67 个氨基酸残基。经与 Kunitz 型肽进行比对,两者具有高度相似性。Cerastokunin 的三维结构中有 12% 的 α 螺旋和 21% 的 β 链,pI 为 8.48。Cerastokunin 可抑制凝血酶和胰蛋白酶的蛋白酶活性,阻断内在和外在凝血途径,从而显示出强大的抗凝作用。在 PT 和 aPPT 中,Cerastokunin 都能以剂量依赖的方式延长凝血时间。如分子对接所示,Cerastokunin 与 Lys48 和 Gln192 直接结合,可抑制凝血酶、Xa 因子和胰蛋白酶。一旦受到凝血酶的刺激,Cerastokunin 就会对 PARs 依赖性途径血小板产生剂量反应性阻断。在一项体内研究中,与抗血栓药物的效果相比,Cerastokunin 浓度的增加可使小鼠卡拉胶模型中的尾部血栓减少更多。在所有 Cerastokunin 剂量(最高达 6 毫克/千克)的试验期间,接受挑战的小鼠均未出现体内毒性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Structural, Biochemical Characterization and Molecular Mechanism of Cerastokunin: A New Kunitz-Type Peptide with Potential Inhibition of Thrombin, Factor Xa and Platelets

Structural, Biochemical Characterization and Molecular Mechanism of Cerastokunin: A New Kunitz-Type Peptide with Potential Inhibition of Thrombin, Factor Xa and Platelets

Structural, Biochemical Characterization and Molecular Mechanism of Cerastokunin: A New Kunitz-Type Peptide with Potential Inhibition of Thrombin, Factor Xa and Platelets

The current investigation focused on separating Cerastes cerastes venom to produce the first Kunitz-type peptide. Based on its anti-trypsin effect, Cerastokunin, a 7.75 kDa peptide, was purified until homogenity by three steps of chromatography. Cerastokunin was found to include 67 amino acid residues that were obtained by de novo sequencing using LC-MALDI-MSMS. Upon alignment with Kunitz-type peptides, there was a high degree of similarity. Cerastokunin’s 3D structure had 12% α-helices and 21% β-strands with pI 8.48. Cerastokunin showed a potent anticoagulant effect by inhibiting the protease activity of thrombin and trypsin as well as blocking the intrinsic and extrinsic coagulation pathways. In both PT and aPPT, Cerastokunin increased the blood clotting time in a dose-dependent way. Using Lys48 and Gln192 for direct binding, Cerastokunin inhibited thrombin, Factor Xa and trypsin as shown by molecular docking. Cerastokunin exhibited a dose–response blockade of PARs-dependent pathway platelet once stimulated by thrombin. An increased concentration of Cerastokunin resulted in a larger decrease of tail thrombus in the mice-carrageenan model in an in vivo investigation when compared to the effects of antithrombotic medications. At all Cerastokunin doses up to 6 mg/kg, no in vivo toxicity was seen in challenged mice over the trial’s duration.

Graphical Abstract

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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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