Curcumin-like diarylpentanoid analogues exhibit antiviral and anti-inflammatory activities in influenza A virus-infected A549 lung epithelial cells by inhibiting multiple retinoic acid-inducible gene I (RIG-I)-mediated pathways

Influenza A virus (IAV) causes seasonal epidemics and occasionally pandemics. Curcumin, a well-known phytochemical, has been reported to exhibit anti-IAV effects; however, most studies were not comprehensive and utilized Mardin-Darby canine kidney (MDCK) cells. Curcumin-like diarylpentanoid analogues, namely 2-benzoyl-6-(3,4-dihydroxybenzylidene)cyclohexen-1-ol (BDHBC) and 5-(3,4-dihydroxyphenyl)-3-hydroxy-1-(2-hydroxyphenyl)penta-2,4-dien-1-one (DHHPD), exhibit improved drug-like properties, including increased solubility and stability, along with stronger antiviral effects against rhinovirus (RV). Thus, this study evaluates the antiviral and anti-inflammatory activities of BDHBC and DHHPD using A549 lung epithelial cells infected with influenza A/Puerto Rico/8/34 (H1N1), and compared their antiviral effects with curcumin in different treatment modes (pre-, co- and post-treatment). Like curcumin, BDHBC and DHHPD significantly reduced virus yield in the post-treatment mode and exhibited direct virucidal activity. Post-treatment with BDHBC and DHHPD also significantly suppressed viral replication as well as pro-inflammatory cytokines (IL-6, IL-8 and IP-10) and interferons (IFN-β and IFN-λ1) at both the gene and protein levels. The stronger antiviral and anti-inflammatory effects of DHHPD were attributed to its inhibition of multiple retinoic acid-inducible gene I (RIG-I)-mediated signalling pathways, including NF-κB, AP-1, MAPKs (p38 and Erk1/2), IRF3 and Akt. Only some of these pathways were affected by BDHBC treatment. Neither compound affected RIG-I or IRF7 expression, which is consistent with their lack of impact on Stat1 activation. Interestingly, DHHPD also demonstrated significant prophylactic effect against IAV infection, which was not observed for BDHBC and curcumin. In conclusion, BDHBC and DHHPD inhibit IAV replication and cytokine responses by targeting host signalling pathways. Further investigation in vivo is required.