Indomethacin (INM), a well-known non-steroidal anti-inflammatory drug, has recently gained attention for its antiviral activity demonstrated in drug repurposing studies against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Although the mechanism of action of INM is not yet fully understood, recent studies have indicated that it acts at an early stage of the coronaviruses (CoVs) replication cycle. In addition, a proteomic study reported that the anti-SARS-CoV-2 activity of INM could be also ascribed to its ability to inhibit human prostaglandin E synthase type 2 (PGES-2), a host protein which interacts with the SARS-CoV-2 NSP7 protein. Although INM does not potently inhibit SARS-CoV-2 replication in infected Vero E6 cells, here we have explored for the first time the application of the Proteolysis Targeting Chimeras (PROTACs) technology in order to develop more potent INM-derived PROTACs with anti-CoV activity. In this study, we report the design, synthesis, and biological evaluation of a series of INM-based PROTACs endowed with antiviral activity against a panel of human CoVs, including different SARS-CoV-2 strains. Two PROTACs showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies support human PGES-2 as a potential target of INM-based antiviral PROTACs, thus paving the way toward the development of host-directed anti-CoVs strategies. To the best of our knowledge, these PROTACs represent the first-in-class INM-based PROTACs with antiviral activity and also the first example of the application of PROTACs to develop pan-coronavirus agents.

吲哚美辛 (INM) 是一种众所周知的非甾体类抗炎药，最近因其在针对严重急性呼吸系统综合症冠状病毒-2 (SARS-CoV-2) 的药物再利用研究中证明的抗病毒活性而受到关注。尽管尚未完全了解 INM 的作用机制，但最近的研究表明它在冠状病毒 (CoV) 复制周期的早期阶段起作用。此外，一项蛋白质组学研究报告称，INM 的抗 SARS-CoV-2 活性也可归因于其抑制人前列腺素 E 合酶 2 型 (PGES-2) 的能力，PGES-2 是一种与 SARS-CoV 相互作用的宿主蛋白-2 NSP7 蛋白。尽管 INM 不能有效抑制 SARS-CoV-2 在受感染的 Vero E6 细胞中的复制，在这里，我们首次探索了蛋白水解靶向嵌合体 (PROTACs) 技术的应用，以开发更有效的具有抗 CoV 活性的 INM 衍生 PROTACs。在这项研究中，我们报告了一系列基于 INM 的 PROTAC 的设计、合成和生物学评估，这些 PROTAC 具有针对一组人类 CoV（包括不同的 SARS-CoV-2 毒株）的抗病毒活性。与 INM 相比，两种 PROTAC 的抗病毒效力显着提高。分子模型研究支持人类 PGES-2 作为基于 INM 的抗病毒 PROTAC 的潜在靶标，从而为开发宿主导向的抗冠状病毒策略铺平了道路。据我们所知，