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、分泌的蛋白质，是炎症的主要驱动力，通过与GPCRs结合来招募免疫炎症细胞到受损组织。扁虱在唾液中分泌一种名为EVASIN的小蛋白质，这种蛋白质能够结合和中和多种趋化因子，从而使宿主趋化因子网络失效。这一特性使扁虱可以在不被检测到的情况下进食数天。Evasins已被证明在临床前模型中具有强大的抗炎作用，包括在心肌梗死和斑块炎症中。到目前为止，已经从多个扁虱物种中鉴定出40多个扁虱EVASIN，所有这些都具有广泛和混杂的趋化因子结合特性。我们的目标是利用化学和结构生物学技术研究EVASIN和趋化因子之间的相互作用界面的性质。蛋白质片段将被用来了解伊瓦菌素的多趋化因子结合特性的分子基础，并研究伊瓦菌素如何中和趋化因子的功能。我们还旨在通过化学合成对片段/蛋白质的修饰来更多地了解这些相互作用的选择性，扩大我们开发化学探针的理论基础。通过使用这些化学探针绘制这些蛋白质之间的相互作用图，我们希望能够了解这些相互作用是如何被模拟的。

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.