Title: Mechanism-based Covalent Neuraminidase Inhibitors with Broad Spectrum Influenza Antiviral Activity

Influenza antiviral agents play important roles in modulating disease severity and in controlling pandemics while vaccines are prepared, but the development of resistance to agents like the commonly used neuraminidase inhibitor Tamiflu may limit their future utility. We report here a completely new class of specific, mechanism-based anti-influenza drugs that function via the formation of a highly stabilized covalent intermediate in the neuraminidase enzyme, and confirm this mode of action via structural and mechanistic studies. These compounds function not only in cell-based assays, but also in animal models, with efficacies comparable to that of Relenza and with broad spectrum activity against drug-resistant strains in vitro. With their great structural similarity to the natural substrate, and their novel mode of action based upon the enzyme mechanism, this class of drug should be less prone to resistance development, offering a new approach to the control of influenza.