Zanamivir and oseltamivir are pnncipal influenza antiviral drugs that target viral neuraminidase (NA), but resistant viruses containing mutant NAs with diminished drug affinity are increasingly emerging.Using the structural knowledge of both drug-binding sites and their spatial arrangement on the homotetrameric NA, we have developed a tetravalent zanamivir (TZ) molecule that exhibited marked increases in NA binding affinity, inhibition of NA enzyme activity, and in vitro plus in vivo antiviral efficacy over zanamivir.TZ functioned against both human seasonal H3N2 and avian H7N9 viruses,including drug-resistant mutants.Crystal structure of a resistant N9 NA in complex with TZ explained the function, which showed that four zanamivir residues simultaneously bound to all four monomers of NA.The design method of TZ described in this study may be useful to develop drugs or ligands that target proteins with multiple binding sites.The potent anti-influenza activity of TZ makes it attractive for further development.
Lifeng Fu Yuhai Bi Yan Wu Shanshan Zhang Jianxun Qi Yah Li Xuancheng Lu Zhenning Zhang Xun Lv Jinghua Yan George F.Gao Xuebing Li
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Changping District, Bei CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Aca