Targeting the lipid membrane to prevent viral entry: the case of a C18-alkylated EGCG compound

Viruses depend on host cell membrane trafficking machinery for most stages of their life cycle, including viral entry, assembly, and immune evasion. Accordingly, alteration in membrane lipid composition and organization may impair viral access to host cells. In this work, we synthesized a series of lipophilic derivatives of Epigallocatechin-3-gallate (EGCG) and evaluated their SARS-CoV-2 inhibitory activity in an in vitro model. Among them, EGCG-C18, a 4″-octadecyl EGCG derivative obtained by regio-selective alkylation of the natural polyphenol resulted as the most promising drug candidate. The localization of EGCG-C18 within the cell membrane was assessed by Fourier Transform InfraRed and Raman Microspectroscopy (FTIRM and RMS), while its interaction with monosialotetrahexosylganglioside (GM1), a glycosphingolipid present in specific microdomains of the plasma membrane, known as lipid rafts, was investigated using Molecular Dynamics (MD) simulation, flow cytometry, and confocal microscopy. EGCG-C18 seems to prevent viruses from entering cells by directly impacting the organization of GM1. In addition, we demonstrated that EGCG-C18 treatment decreases EGFR activation, introducing other potential actions of this compound. Finally, EGCG-C18 was evaluated against Herpes Simplex, Influenza B, and HIV-1, to test the hypothesis of a broad-spectrum antiviral activity, potentially driven by its ability to reorganize lipid raft components.