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With regular influenza epidemics and the prevalence of drug-resistant influenza virus strains, it is extremely crucial to develop effective and low-toxicity anti-influenza A virus drugs that act on conserved sites of novel targets. Here, we found a new anti-influenza virus compound, 1,3-dihydroxy-6-benzo[ c]chromene (D715-2441), from a library of 8026 small-molecule compounds by cell-based MTT assay and explored the underlying mechanisms. Our results revealed that D715-2441 possessed antiviral activities against multiple subtypes of influenza A viruses (IAVs) strains, including H1N1, H5N1, H7N9, H3N2, the clinical isolate 690 (H3), and oseltamivir-resistant strains with the H274Y NA mutation, and suppressed the early steps in the virus replication cycle. Further mechanistic studies indicated that D715-2441 clearly inhibited viral polymerase activity and directly influenced the location of the PB2 protein. Moreover, binding affinity analyses confirmed that D715-2441 bound specifically to the PB2cap protein. Further, protein sequence alignment and a computer-aided molecular docking indicated that highly conserved amino acid residues in the cap-binding pocket of PB2cap were possible binding sites for D715-2441, which indicates that D715-2441 might be employed as a cap-binding competitor. Moreover, the combination of D715-2441 and zanamivir possessed a remarkable synergistic antiviral effect, with an FICI value of 0.40. In conclusion, these results strongly suggest that D715-2441 has potential as a promising candidate against IAV infection. More importantly, our work offers novel options for the strategic development of PB2cap inhibitors of IAV.

Methyl brevifolincarboxylate (MBC) was isolated from ethyl acetate extract of Canarium album (Lour.) Raeusch. The structure was identified, and the effect on influenza A virus infection was evaluated. MBC exhibited inhibitory activity against influenza virus A/Puerto Rico/8/34 (H1N1) and A/Aichi/2/68 (H3N2) with IC50 values of 27.16 ± 1.39 μM and 33.41 ± 2.34 μM. Mechanism studies indicated that MBC inhibited the replication of influenza A virus by targeting PB2 cap‐binding domain. Our results demonstrated MBC was a potent PB2 cap‐binding inhibitor and represented as a new type of promising lead compound for the development of anti‐influenza virus drugs from natural products.

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