Lycorine derivative effectively inhibits the replication of coronaviruses both in vitro and in vivo

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 low 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.