5JYY

Structure-based Tetravalent Zanamivir with Potent Inhibitory Activity against Drug-resistant Influenza Viruses

Replaces:  5E6L

Summary for 5JYY

• Entry DOI: 10.2210/pdb5jyy/pdb
• Related: 4MWX
• Descriptor: Neuraminidase, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: neuraminidase inhibitor, tetravalent zanamivir, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus
• Total number of polymer chains: 1
• Total formula weight: 46000.79

Authors

Fu, L.,Wu, Y.,Bi, Y.,Zhang, S.,Lv, X.,Qi, J.,Li, Y.,Lu, X.,Yan, J.,Gao, G.F.,Li, X. (deposition date: 2016-05-15, release date: 2016-06-29, Last modification date: 2024-11-06)

Primary citation

Fu, L.,Bi, Y.,Wu, Y.,Zhang, S.,Qi, J.,Li, Y.,Lu, X.,Zhang, Z.,Lv, X.,Yan, J.,Gao, G.F.,Li, X.
Structure-Based Tetravalent Zanamivir with Potent Inhibitory Activity against Drug-Resistant Influenza Viruses
J.Med.Chem., 59:6303-6312, 2016

PubMed Abstract: Zanamivir and oseltamivir are principal 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.

PubMed: 27341624
DOI: 10.1021/acs.jmedchem.6b00537

Experimental method

X-RAY DIFFRACTION (2.1 Å)