摘要The established and ongoing prevalence of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)and sea-sonal 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 pre-vious 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 ly-corine 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 develop-ment of broad-spectrum anti-coronavirus drugs.