8SD2

Crystal structure of the A/Puerto Rico/8/1934 (H1N1) influenza virus hemagglutinin in complex with small molecule fusion inhibitor compound 4

8SD2 の概要

• エントリーDOI: 10.2210/pdb8sd2/pdb
• 関連するPDBエントリー: 5W5S
• 分子名称: Hemagglutinin HA1 chain, Hemagglutinin HA2 chain, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: influenza virus, fusion inhibitor, antiviral protein
• 由来する生物種: Influenza A virus (strain A/Puerto Rico/8/1934 H1N1); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 58275.53

構造登録者

Kadam, R.U.,Zhu, X.Y.,Wilson, I.A. (登録日: 2023-04-06, 公開日: 2024-06-05, 最終更新日: 2024-10-23)

主引用文献

Kitamura, S.,Lin, T.H.,Lee, C.D.,Takamura, A.,Kadam, R.U.,Zhang, D.,Zhu, X.,Dada, L.,Nagai, E.,Yu, W.,Yao, Y.,Sharpless, K.B.,Wilson, I.A.,Wolan, D.W.
Ultrapotent influenza hemagglutinin fusion inhibitors developed through SuFEx-enabled high-throughput medicinal chemistry.
Proc.Natl.Acad.Sci.USA, 121:e2310677121-e2310677121, 2024

PubMed Abstract: Seasonal and pandemic-associated influenza strains cause highly contagious viral respiratory infections that can lead to severe illness and excess mortality. Here, we report on the optimization of our small-molecule inhibitor F0045(S) targeting the influenza hemagglutinin (HA) stem with our Sulfur-Fluoride Exchange (SuFEx) click chemistry-based high-throughput medicinal chemistry (HTMC) strategy. A combination of SuFEx- and amide-based lead molecule diversification and structure-guided design led to identification and validation of ultrapotent influenza fusion inhibitors with subnanomolar EC cellular antiviral activity against several influenza A group 1 strains. X-ray structures of six of these compounds with HA indicate that the appended moieties occupy additional pockets on the HA surface and increase the binding interaction, where the accumulation of several polar interactions also contributes to the improved affinity. The compounds here represent the most potent HA small-molecule inhibitors to date. Our divergent HTMC platform is therefore a powerful, rapid, and cost-effective approach to develop bioactive chemical probes and drug-like candidates against viral targets.

PubMed: 38753503
DOI: 10.1073/pnas.2310677121

実験手法

X-RAY DIFFRACTION (2.81 Å)