Harnessing hydrophobic tag technology to combat drug-resistant influenza: design, synthesis and potency of oseltamivir-derived HyTTDs†

Influenza, driven by highly mutable RNA viruses, poses a major global health threat, exacerbated by the frequent emergence of antiviral resistance. To tackle this challenge, we developed hydrophobic tag tethering degradation (HyTTD) technology to enhance the efficacy of oseltamivir against resistant strains. Among these, compound L12, featuring a 1-adamantylamine hydrophobic tag attached via a nine-carbon linker, demonstrated exceptional antiviral activity, with a 157-fold improvement in potency (EC₅₀ = 0.68 μM) against the oseltamivir-resistant H1N1-H274Y strain compared to oseltamivir (EC₅₀ = 106.8 μM), and minimal cytotoxicity at 50 μM. Western blot and immunofluorescence analyses demonstrated that L12 selectively induced the degradation of viral neuraminidase (NA) and inhibited nucleoprotein (NP) expression in a dose-dependent manner. Mechanistic studies revealed that L12 did not interfere with NA synthesis but promotes NA protein degradation through ubiquitination. These results highlight the pioneering application of HyTTD in overcoming antiviral resistance, showcasing it as a powerful platform for future drug development.