Stapled peptides as a new technology to investigate protein-protein interactions in human platelets.
Stapled peptides as a new technology to investigate protein-protein interactions in human platelets.
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DOI：
10.1039/c8sc00284c
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发表时间：
2018-05-28
期刊：
影响因子：
8.4
通讯作者：
Spring DR
中科院分区：
文献类型：
--
作者：
Iegre J;Ahmed NS;Gaynord JS;Wu Y;Herlihy KM;Tan YS;Lopes-Pires ME;Jha R;Lau YH;Sore HF;Verma C;O' Donovan DH;Pugh N;Spring DR
我们描述了钉合肽在人类血小板中的首次应用。 Bim BH3 钉合肽用于克服传统方法的局限性，并揭示 Bim 在血小板活化中的新作用。血小板是在止血、心血管血栓事件和癌症转移中具有许多重要病理生理学作用的血细胞。血小板激活需要参与涉及蛋白质-蛋白质相互作用 (PPI) 的细胞内信号传导途径。因此，更好地了解这些途径对于开发选择性抗血小板药物至关重要。研究人类血小板中质子泵抑制剂的新策略需要克服传统血小板研究方法的局限性。例如，小分子抑制剂可能缺乏选择性，并且通常难以设计和合成。此外，转基因动物模型的开发成本高昂且耗时，并且由于血小板中缺乏细胞核，传统的重组技术是无效的。在此，我们描述了新型功能化钉合肽库的生成及其在血小板 PPI 研究中的首次应用。此外，血小板渗透性钉合 Bim BH3 肽的使用证实了 Bim 在磷脂酰丝氨酸 (PS) 暴露中的作用，并揭示了 Bim 蛋白在血小板激活过程中的作用。我们的工作表明，功能化的钉合肽是传统血小板研究方法的补充替代方案，并且可以为了解血小板信号传导途径以及抗血小板药物的开发做出重大贡献。
We describe the first application of stapled peptides in human platelets. Bim BH3 stapled peptides are used to overcome the limitations of traditional methods and uncover a new role for Bim in platelet activation. Platelets are blood cells with numerous crucial pathophysiological roles in hemostasis, cardiovascular thrombotic events and cancer metastasis. Platelet activation requires the engagement of intracellular signalling pathways that involve protein–protein interactions (PPIs). A better understanding of these pathways is therefore crucial for the development of selective anti-platelet drugs. New strategies for studying PPIs in human platelets are required to overcome limitations associated with conventional platelet research methods. For example, small molecule inhibitors can lack selectivity and are often difficult to design and synthesise. Additionally, development of transgenic animal models is costly and time-consuming and conventional recombinant techniques are ineffective due to the lack of a nucleus in platelets. Herein, we describe the generation of a library of novel, functionalised stapled peptides and their first application in the investigation of platelet PPIs. Moreover, the use of platelet-permeable stapled Bim BH3 peptides confirms the part of Bim in phosphatidyl-serine (PS) exposure and reveals a role for the Bim protein in platelet activatory processes. Our work demonstrates that functionalised stapled peptides are a complementary alternative to conventional platelet research methods, and could make a significant contribution to the understanding of platelet signalling pathways and hence to the development of anti-platelet drugs.
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