Inhibition of influenza A virus replication by a marine derived quinolone alkaloid targeting virus nucleoprotein

Abstract Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti‐influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, a novel quinolone alkaloid (QLA) derived from marine fungus was discovered with broad‐spectrum anti‐IAV activities with low toxicity. Distinct from current anti‐IAV drugs, QLA may block virus replication and viral RNA (vRNA) export from the nucleus by targeting virus nucleoprotein (NP). QLA can block the binding of chromosome region maintenance 1 to nuclear export signal 3 of NP to inhibit the nuclear export of NP and vRNP. QLA may also affect vRNP assembly by interfering with the binding of NP to RNA rather than NP oligomerization. Arg305 and Phe488‐Gly490 may be required for the interaction between QLA and NP, and the binding pocket around these amino acids may be a promising target for anti‐IAV drugs. Importantly, oral administration of QLA can protect the mice against IAV‐induced death and weight loss, superior to the effects of the clinical drug oseltamivir. In summary, the marine derived compound QLA has the potential to be developed into a novel anti‐IAV agent targeting virus NP protein in the future.