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A DARPin targeting activated Mac-1 is a novel diagnostic tool and potential anti-inflammatory agent in myocarditis, sepsis and myocardial infarction
Basic Research in Cardiology ( IF 9.5 ) Pub Date : 2021-03-15 , DOI: 10.1007/s00395-021-00849-9
Patrick M Siegel 1, 2 , István Bojti 1 , Nicole Bassler 2 , Jessica Holien 3 , Ulrike Flierl 2 , Xiaowei Wang 2, 4, 5 , Philipp Waggershauser 1 , Xavier Tonnar 1 , Christopher Vedecnik 1 , Constanze Lamprecht 6 , Ivana Stankova 1 , Tian Li 1 , Thomas Helbing 1 , Dennis Wolf 1 , Nathaly Anto-Michel 1 , Lucia Sol Mitre 1 , Julia Ehrlich 1 , Lukas Orlean 1 , Ileana Bender 1 , Anne Przewosnik 1 , Maximilian Mauler 1 , Laura Hollederer 1 , Martin Moser 1 , Christoph Bode 1 , Michael W Parker 3, 4, 7 , Karlheinz Peter 2, 4, 5, 8 , Philipp Diehl 1, 2, 5
Affiliation  

The monocyte β2-integrin Mac-1 is crucial for leukocyte–endothelium interaction, rendering it an attractive therapeutic target for acute and chronic inflammation. Using phage display, a Designed-Ankyrin-Repeat-Protein (DARPin) was selected as a novel binding protein targeting and blocking the αM I-domain, an activation-specific epitope of Mac-1. This DARPin, named F7, specifically binds to activated Mac-1 on mouse and human monocytes as determined by flow cytometry. Homology modelling and docking studies defined distinct interaction sites which were verified by mutagenesis. Intravital microscopy showed reduced leukocyte–endothelium adhesion in mice treated with this DARPin. Using mouse models of sepsis, myocarditis and ischaemia/reperfusion injury, we demonstrate therapeutic anti-inflammatory effects. Finally, the activated Mac-1-specific DARPin is established as a tool to detect monocyte activation in patients receiving extra-corporeal membrane oxygenation, as well as suffering from sepsis and ST-elevation myocardial infarction. The activated Mac-1-specific DARPin F7 binds preferentially to activated monocytes, detects inflammation in critically ill patients, and inhibits monocyte and neutrophil function as an efficient new anti-inflammatory agent.



中文翻译:

靶向激活的 Mac-1 的 DARPin 是一种新型诊断工具和潜在的心肌炎、败血症和心肌梗塞抗炎剂

单核细胞β2-整合素Mac-1对于白细胞-内皮相互作用至关重要,使其成为急性和慢性炎症的有吸引力的治疗靶点。使用噬菌体展示,选择设计的锚蛋白重复蛋白 (DARPin) 作为靶向和阻断 α M的新型结合蛋白I 域,Mac-1 的激活特异性表位。这种名为 F7 的 DARPin 与小鼠和人类单核细胞上的活化 Mac-1 特异性结合,通过流式细胞术确定。同源建模和对接研究定义了通过诱变验证的不同相互作用位点。活体显微镜显示用这种 DARPin 治疗的小鼠白细胞 - 内皮细胞粘附减少。使用败血症、心肌炎和缺血/再灌注损伤的小鼠模型,我们展示了治疗性抗炎作用。最后,激活的 Mac-1 特异性 DARPin 被确立为检测接受体外膜氧合以及患有败血症和 ST 段抬高心肌梗塞的患者单核细胞活化的工具。活化的 Mac-1 特异性 DARPin F7 优先与活化的单核细胞结合,

更新日期:2021-03-15
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