PDF(Pubmed)
Abstract：
Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV.
摘要：
寨卡病毒（ZIKV）是一种重新出现的RNA病毒，已知会导致婴儿的眼部和神经系统异常。ZIKV利用感染细胞中的自噬过程来增强其复制和传播。因此，自噬抑制剂已成为对抗RNA病毒的有效治疗靶点，羟氯喹（HCQ）是最有希望的候选之一。在这项研究中,我们合成了几种新型的小分子喹啉衍生物，评估他们的抗病毒活性，并确定了潜在的分子机制。在九种合成的类似物中，两位主要候选人,标记为GL-287和GL-382，显著减弱ZIKV在人类眼细胞中的复制，主要通过抑制自噬。这两种化合物的抗病毒功效超过了HCQ和其他现有的自噬抑制剂，如ROC-325、DC661和GNS561。此外，与HCQ不同,这些新的类似物在眼细胞中没有表现出细胞毒性。在ZIKV感染的细胞中用化合物GL-287和GL-382处理增加了LC3斑点的丰度，表明自噬过程的中断。此外，化合物GL-287和GL-382可有效抑制ZIKV诱导的眼细胞先天炎症反应。总的来说，我们的研究证明了新型自噬抑制剂对ZIKV具有安全有效的抗病毒活性.
