Vertebrate organisms express a diversity of protein receptors that recognize and respond to the presence of pathogenic molecules, functioning as an early warning system for infection. As a result of mutation or dysregulated metabolism, these same innate immune receptors can be inappropriately activated, leading to inflammation and disease. One of the most important receptors for detection and response to RNA viruses is called RIG-I, and dysregulation of this protein is linked with a variety of disease states. Despite its central role in inflammatory responses, antagonists for RIG-I are underdeveloped. In this study, we use invitro selection from a pool of modified DNA aptamers to create a high affinity RIG-I antagonist. A high resolution crystal structure of the complex reveals molecular mimicry between the aptamer and the 5′-triphosphate terminus of viral ligands, which bind to the same amino acids within the CTD recognition platform of the RIG-I receptor. Our study suggests a powerful, generalizable strategy for generating immunomodulatory drugs and mechanistic tool compounds.

脊椎动物表达多种蛋白质受体，这些受体可识别致病分子的存在并做出反应，充当感染的早期预警系统。由于突变或代谢失调，这些先天免疫受体可能会被不适当地激活，导致炎症和疾病。 RIG-I 是检测和响应 RNA 病毒的最重要受体之一，这种蛋白质的失调与多种疾病状态有关。尽管 RIG-I 在炎症反应中发挥着核心作用，但 RIG-I 的拮抗剂尚未开发出来。在这项研究中，我们使用从修饰 DNA 适体池中进行体外选择来创建高亲和力 RIG-I 拮抗剂。该复合物的高分辨率晶体结构揭示了适体和病毒配体的5'-三磷酸末端之间的分子模拟，病毒配体与RIG-I受体的CTD识别平台内的相同氨基酸结合。我们的研究提出了一种强大的、通用的策略来生成免疫调节药物和机械工具化合物。