Rhinoviruses (RVs) are the pathogens most often responsible for the common cold, and are a frequent cause of exacerbations in asthma, chronic obstructive pulmonary disease and cystic fibrosis. Here we report the discovery of IMP-1088, a picomolar dual inhibitor of the human N-myristoyltransferases NMT1 and NMT2, and use it to demonstrate that pharmacological inhibition of host-cell N-myristoylation rapidly and completely prevents rhinoviral replication without inducing cytotoxicity. The identification of cooperative binding between weak-binding fragments led to rapid inhibitor optimization through fragment reconstruction, structure-guided fragment linking and conformational control over linker geometry. We show that inhibition of the co-translational myristoylation of a specific virus-encoded protein (VP0) by IMP-1088 potently blocks a key step in viral capsid assembly, to deliver a low nanomolar antiviral activity against multiple RV strains, poliovirus and foot and-mouth disease virus, and protection of cells against virus-induced killing, highlighting the potential of host myristoylation as a drug target in picornaviral infections.

鼻病毒 (RV) 是最常引起普通感冒的病原体，也是哮喘、慢性阻塞性肺病和囊性纤维化恶化的常见原因。在这里，我们报告了 IMP-1088 的发现，它是人N -肉豆蔻酰基转移酶 NMT1 和 NMT2 的皮摩尔双重抑制剂，并用它来证明对宿主细胞N -肉豆蔻酰化的药理抑制可以快速、完全地阻止鼻病毒复制，而不诱导细胞毒性。弱结合片段之间协同结合的识别导致通过片段重建、结构引导片段连接和对连接体几何形状的构象控制来快速优化抑制剂。我们发现，IMP-1088 抑制特定病毒编码蛋白 (VP0) 的共翻译肉豆蔻酰化，可有效阻断病毒衣壳组装的关键步骤，从而针对多种 RV 病毒株、脊髓灰质炎病毒和足部病毒提供低纳摩尔抗病毒活性。口病病毒，以及保护细胞免受病毒诱导的杀伤，强调了宿主肉豆蔻酰化作为小核糖核酸病毒感染的药物靶点的潜力。