Institute of Medical Sciences, University of Aberdeen, Ashgrove Road West, Aberdeen AB25 2ZD, UK.
Marine Biodiscovery Centre, Department of Chemistry, University of Aberdeen, Meston Walk, Aberdeen AB24 3UE, UK.
Molecules. 2020 Feb 19;25(4):922. doi: 10.3390/molecules25040922.
As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein-protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide.
与小分子不同，大环肽具有较大的表面积，被认为是通过破坏特定的蛋白质-蛋白质相互作用（PPIs）来有选择性地治疗疾病的有前途的候选物。由于难以预测溶液中环肽的构象，因此生物活性环肽的从头设计仍然具有很大的挑战性。在这项研究中，我们使用构象分析和分子对接研究的组合来设计一种新的环肽抑制剂，用于抑制人肿瘤坏死因子α（TNFα）与其受体 TNFR-1 之间的相互作用。这种相互作用是介导人类组织损伤和感染的炎症反应的关键，也是类风湿关节炎、银屑病和炎症性肠病的重要致病因素。确定了环肽的溶液状态 NMR 结构，这有助于推断其与 TNFα 的相互作用模式。使用 TNFα 传感器细胞来评估肽的生物学活性。
