Lycorine derivative effectively inhibits the replication of coronaviruses both in vitro and in vivo
Liang Shen, Jianzhong Zhao, Ying Xia, Junjie Lu, Jiali Sun, Jian Tang, Hui Xing, Lijuan Yin, Yang Yang, Chunhua Wang
Abstract
The established and ongoing prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seasonal human coronaviruses (HCoV) like HCoV-OC43, HCoV-NL63 and HCoV-229E, pose a continuous threat to public health. Therefore, it is urgently needed to explore antiviral drugs with broad-spectrum anti-coronavirus activity. Our previous studies have revealed that lycorine is a potent broad-spectrum anti-coronavirus drug, a natural alkaloid extracted from Amaryllidaceae with various pharmacological and microbiological effects. However, it is unsafe to directly use lycorine as a clinical antiviral drug due to the cytotoxicity and induction of cell apoptosis. In this study, a series of lycorine derivatives were designed and synthesized. One of them, named Ly-8, was found to effectively inhibit the replication of different coronavirus strains in vitro, including SARS-CoV-2. Moreover, Ly-8 was also shown to effectively inhibit HCoV-OC43 replication in the central nervous system, and provide effective protection against HCoV-OC43 infection in mice with lower drug toxicity. Furthermore, Ly-8-resistant mutants were not observed during the 30 times sequential passages in cell culture. Collectively, these findings suggest that Ly-8 may be a potential candidate drug for the future development of broad-spectrum anti-coronavirus drugs.