5JYY

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

「5E6L」から置き換えられました

5JYY の概要

• エントリーDOI: 10.2210/pdb5jyy/pdb
• 関連するPDBエントリー: 4MWX
• 分子名称: 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)
• 機能のキーワード: neuraminidase inhibitor, tetravalent zanamivir, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46000.79

構造登録者

Fu, L.,Wu, Y.,Bi, Y.,Zhang, S.,Lv, X.,Qi, J.,Li, Y.,Lu, X.,Yan, J.,Gao, G.F.,Li, X. (登録日: 2016-05-15, 公開日: 2016-06-29, 最終更新日: 2024-11-06)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.1 Å)