Abstract
Betacoronaviruses encompass a spectrum of respiratory diseases, from common cold caused by the human coronavirus (HCoV)-OC43 to life-threatening severe acute respiratory syndrome (SARS)-CoV-2. Addressing the constant need for novel antiviral compounds, we turned to the exploration of 40 plant-specialized metabolites produced by the medicinal plant family Amaryllidaceae, known to produce lycorine, a strong antiviral alkaloid. The present screen included 35 alkaloids with representatives of 8 ring-type structures. Pancracine, crinamine, hemanthamine, and hemanthidine exhibited potency comparable to lycorine in blocking HCoV-OC43 replication, while amarbellisine demonstrated superior efficacy (SI = 60, EC(50) = 0.2 μM). Their anticoronaviral activity was confirmed using a SARS-CoV-2 replicon system. Time-of-drug-addition experiments established that a postentry step consistent with ribonucleic acid (RNA) replication or translation was targeted. Most antiviral Amaryllidaceae alkaloids selectively induced the expression of transcripts associated with the integrated stress response. Structure-activity relationship analyses elucidated key functional groups contributing to antiviral properties in the crinine- and lycorine-type. This study reveals that Amaryllidaceae produce a diverse repertoire of promising antiviral compounds in addition to lycorine, offering insights for developing new antiviral agents.