Fusion Inhibition of Zika Virus Entry by a Teicoplanin Pseudoaglycone Derivative with Broad Antiviral Activity

Background/Objectives: The lack of effective antiviral therapies for many viral infections highlights the need for the development of new antiviral agents. The broad antiviral effects of glycopeptide antibiotics (GPAs) and their derivatives have been previously described. In our studies, we investigated the in vitro viral inhibitory activity of newly synthesized GPA derivatives against Zika virus (ZIKV), chikungunya virus (CHIKV), o'nyong-nyong virus (ONNV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods: Antiviral activity (EC50) and cytotoxicity (CC50) of the active compounds were determined using cell-based assays. The mechanism of action of the lead compound was investigated using binding and entry assays, cell-free virion pre-incubation, a virion destabilization assay, a liposome-based capsid protection assay, and molecular docking analysis. Results: Seven of the compounds were able to inhibit ZIKV and two compounds inhibited all four tested viruses. Among them, a teicoplanin pseudoaglycone derivative, compound 7, showed the strongest antiviral activity, inhibiting all four viruses at low micromolar concentrations. Mechanistic studies demonstrated that compound 7 acts during an early stage of ZIKV infection and inhibits low-pH-triggered virus-liposome fusion. Molecular docking analysis suggested potential interactions between compound 7 and the viral envelope protein that could interfere with the conformational rearrangements required for membrane fusion. Conclusions: The present findings demonstrate that hydrophobic GPA derivatives, particularly compound 7, exhibit promising broad-spectrum antiviral activity in vitro. Whether similar mechanisms contribute to the antiviral activity against other viruses remains unknown. The studied GPA derivatives are promising candidates for further pre-clinical and clinical development as broad-spectrum antivirals.