Exploring the anti-influenza virus activity of novel triptolide derivatives targeting nucleoproteins.

[Display omitted] • Novel series of triptolide derivatives were designed and synthesized. • Triptolide derivatives were exhibited activities against influenza A virus. • TPDMSA suppressed influenza A virus replication through inhibiting ribonucleoprotein complex nucleus export. • TPDMSA downregulated influenza A virus-induced macrophage cytokine storm. Triptolide (TP) is a major active compound derived from the traditional Chinese medicine Tripterygium wilfordii. TP has been reported to inhibit the infection of HIV and a few other viruses. However, the antiviral spectrum and the underlying mechanisms of TP are incompletely defined. TP derivatives were designed, synthesized, and evaluated for anti-influenza activity against the influenza A virus in this study. All of them exhibited activities against oseltamivir sensitive influenza A/WSN/33 virus (H1N1) and oseltamivir resistant influenza A/PR/8/33 virus (H1N1) with low cytotoxicity in vitro. In our present study, TP derivatives probably suppressed influenza virus replication through inhibiting ribonucleoprotein complex nucleus export of influenza A virus by binding with viral nucleoprotein. Moreover, TP derivatives downregulated influenza A virus-induced macrophage cytokine storm in a dose-dependent manner, through inhibiting nuclear factor kappa-light-chain-enhancer of activated B cell (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasome signaling. Taken together, TP derivatives suppressed influenza A virus replication by directly targeting NP and regulating innate immune responses induced by influenza A virus infection, which suggested that TP derivatives might be prospective candidates for potent antivirals. [ABSTRACT FROM AUTHOR]