Understanding the molecular basis of how the chemokine network is targeted by evasin proteins from tick saliva

趋化因子是一种小的分泌蛋白，是炎症的主要驱动因素，通过与gpcr结合，将免疫炎症细胞招募到受损组织中。蜱虫在唾液中分泌一种叫做evasins的小蛋白质，这种蛋白质有能力结合和中和多种趋化因子，从而使宿主的趋化因子网络失效。这一特性使蜱虫可以连续数日进食而不被发现。在临床前模型中，Evasins已被证明具有有效的抗炎作用，包括心肌梗死和斑块炎症。迄今为止，已经鉴定出来自多种蜱类的40多种蜱逃避，它们都具有广泛和混杂的趋化因子结合特性。我们的目的是利用化学和结构生物学技术研究evasins和趋化因子之间相互作用界面的性质。蛋白质片段将用于了解evasins的多趋化因子结合特性的分子基础，并研究evasins如何中和趋化因子的功能。我们还旨在通过化学合成修饰片段/蛋白质来更多地了解这些相互作用的选择性，从而扩展我们开发化学探针的基本原理。通过使用这些化学探针绘制这些蛋白质之间的相互作用，我们希望了解这些相互作用是如何被模仿的。

Chemokines are small, secreted proteins that are major drivers of inflammation, functioning via binding to GPCRs to recruit immune-inflammatory cells to damaged tissues. Ticks secrete small proteins called evasins, in saliva, that have the ability to bind and neutralise multiple chemokines, thus disabling the host chemokine network. This property allows ticks to feed for days without detection. Evasins have been shown to have potent anti-inflammatory effects in preclinical models, including in myocardial infarction and plaque inflammation. Over 40 tick evasins from multiple tick species have been identified to date, all with broad and promiscuous chemokine binding properties. We aim to study the properties of the interaction interfaces between evasins and chemokines using chemical and structural biology techniques. Protein fragments will be employed to understand the molecular basis of the multi-chemokine binding properties of evasins, and to investigate how evasins neutralise chemokine function. We also aim to understand more about the selectivity of these interactions through modification of fragments/proteins by chemical synthesis, expanding our rationale for chemical probe development. By mapping these protein-protein interactions using these chemical probes we hope to gain an understanding of how these interactions might be mimicked.