Lycorine derivative inhibits SARS-CoV-2 replication by reducing −1 programmed ribosomal frameshifting via targeting ZAP

The ongoing evolution of SARS-CoV-2 and its immune-evading variants underscore the urgent need for broad-spectrum antiviral drugs. This study developed a series of lycorine derivatives, identifying compound 7 as a potent antiviral candidate. Compound 7 demonstrated significant activity against SARS-CoV-2 and its variants both in vitro and in vivo, effectively reducing viral replication and pathological damage in a hamster model. Through further investigation, compelling evidence has been obtained indicating that compound 7 disrupts the SARS-CoV-2 replication by targeting zinc-finger antiviral protein (ZAP) to effectively block the vital –1 programmed ribosomal frameshifting (–1PRF), which is critical for viral replication. This discovery highlights the potential of compound 7 as a novel antiviral candidate that could play a pivotal role in combating SARS-CoV-2 and its emerging variants.