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.