Alkyne-Tagged Apigenin, a Chemical Tool to Navigate Potential Targets of Flavonoid Anti-Dengue Leads

A flavonoid is a versatile core structure with various cellular, immunological, and pharmacological effects. Recently, flavones have shown anti-dengue activities by interfering with viral translation and replication. However, the molecular target is still elusive. Here we chemically modified apigenin by adding an alkyne moiety into the B-ring hydroxyl group. The alkyne serves as a chemical tag for the alkyne-azide cycloaddition reaction for subcellular visualization. The compound located at the perinuclear region at 1 and 6 h after infection. Interestingly, the compound signal started shifting to vesicle-like structures at 6 h and accumulated at 24 and 48 h after infection. Moreover, the compound treatment in dengue-infected cells showed that the compound restricted the viral protein inside the vesicles, especially at 48 h. As a result, the dengue envelope proteins spread throughout the cells. The alkyne-tagged apigenin showed a more potent efficacy at the EC50 of 2.36 & PLUSMN; 0.22, and 10.55 & PLUSMN; 3.37 mu M, respectively, while the cytotoxicities were similar to the original apigenin at the CC50 of 70.34 & PLUSMN; 11.79, and 82.82 & PLUSMN; 11.68 mu M, respectively. Molecular docking confirmed the apigenin binding to the previously reported target, ribosomal protein S9, at two binding sites. The network analysis, homopharma, and molecular docking revealed that the estrogen receptor 1 and viral NS1 were potential targets at the late infection stage. The interactions could attenuate dengue productivity by interfering with viral translation and suppressing the viral proteins from trafficking to the cell surface.

Automated summary

Flavonoids, particularly modified apigenin, show anti-dengue activity by interfering with viral translation. Chemical modification allows for visualization of the compound in subcellular compartments. Molecular docking suggests binding of apigenin to ribosomal protein S9 and potential targets such as estrogen receptor 1 and viral NS1. These interactions attenuate dengue productivity by suppressing viral protein trafficking to the cell surface.