Yi Liang, Wang Yishuai, Wang Jiehuang, Chen Yihan, Huang Weixue, Liao Ying, Zhang Qingwen
Department of Medicinal Chemistry, School of Pharmacy, Shanghai Jiao Tong University Shanghai 200240 China.
State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry Co., Ltd. Shanghai 201203 China
RSC Med Chem. 2024 Dec 23. doi: 10.1039/d4md00846d.
Viral infections trigger the integrated stress response (ISR) in eukaryotic cells that leads to the activation of eIF2α kinases, the elevation of eukaryotic translation initiation factor 2α (eIF2α) phosphorylation, and thereby the shutdown of global protein synthesis that viruses rely on to replicate. Coronaviruses and other viruses have evolved various subversion mechanisms to counteract the antiviral ISR. These intricate host-virus interactions may be exploited by pharmacologically activating the host ISR for the development of host-directed antivirals (HDAs), an increasingly relevant area of research. In this study, we have discovered a new class of flavonoid-based ISR activators that exhibit potent antiviral activity against porcine epidemic diarrhea virus (PEDV) and porcine deltacoronavirus (PDCoV). PEDV and PDCoV are animal coronaviruses of great veterinary and economic importance, for which there are currently no effective therapeutics. The mechanistic study indicated that lead compounds 1-B and 1-C inhibit PEDV and PDCoV replication upregulating eIF2α phosphorylation and thereby downregulating global protein synthesis in host cells, suggesting they are HDA antivirals.
病毒感染会触发真核细胞中的综合应激反应（ISR），导致真核起始因子2α（eIF2α）激酶激活、真核翻译起始因子2α（eIF2α）磷酸化水平升高，从而使病毒赖以复制的整体蛋白质合成停止。冠状病毒和其他病毒已经进化出各种颠覆机制来对抗抗病毒ISR。这些复杂的宿主-病毒相互作用可通过药理学激活宿主ISR来开发宿主导向抗病毒药物（HDA），这是一个越来越相关的研究领域。在本研究中，我们发现了一类新型的基于黄酮类的ISR激活剂，它们对猪流行性腹泻病毒（PEDV）和猪德尔塔冠状病毒（PDCoV）具有强大的抗病毒活性。PEDV和PDCoV是具有重大兽医和经济意义的动物冠状病毒，目前尚无有效的治疗方法。机制研究表明，先导化合物1-B和1-C通过上调eIF2α磷酸化，从而下调宿主细胞中的整体蛋白质合成来抑制PEDV和PDCoV复制，表明它们是HDA抗病毒药物。
