Amaryllidaceae\nAlkaloids Screen Unveils Potent Anticoronaviral\nCompounds and Associated Structural Determinants

Betacoronaviruses encompass a spectrum of respiratory\ndiseases,\nfrom common cold caused by the human coronavirus (HCoV)-OC43 to life-threatening\nsevere acute respiratory syndrome (SARS)-CoV-2. Addressing the constant\nneed for novel antiviral compounds, we turned to the exploration of\n40 plant-specialized metabolites produced by the medicinal plant family\nAmaryllidaceae, known to produce lycorine, a strong antiviral alkaloid.\nThe present screen included 35 alkaloids with representatives of 8\nring-type structures. Pancracine, crinamine, hemanthamine, and hemanthidine\nexhibited potency comparable to lycorine in blocking HCoV–OC43\nreplication, while amarbellisine demonstrated superior efficacy (SI\n= 60, EC<sub>50</sub> = 0.2 μM). Their anticoronaviral activity\nwas confirmed using a SARS-CoV-2 replicon system. Time-of-drug-addition\nexperiments established that a postentry step consistent with ribonucleic\nacid (RNA) replication or translation was targeted. Most antiviral\nAmaryllidaceae alkaloids selectively induced the expression of transcripts\nassociated with the integrated stress response. Structure–activity\nrelationship analyses elucidated key functional groups contributing\nto antiviral properties in the crinine- and lycorine-type. This study\nreveals that Amaryllidaceae produce a diverse repertoire of promising\nantiviral compounds in addition to lycorine, offering insights for\ndeveloping new antiviral agents.