4M3M

Influenza Neuraminidase in complex with a stereomutated analogue of Oseltamivir carboxylate

4M3M の概要

• エントリーDOI: 10.2210/pdb4m3m/pdb
• 分子名称: Neuraminidase, (3R,4S,5S)-4-(acetylamino)-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid, CALCIUM ION, ... (5 entities in total)
• 機能のキーワード: sialidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus
• 細胞内の位置: Host apical cell membrane ; Single-pass type II membrane protein : Q0A480
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43668.16

構造登録者

Kerry, P.S. (登録日: 2013-08-06, 公開日: 2014-02-12, 最終更新日: 2024-11-20)

主引用文献

Sartori, A.,Dell'amico, L.,Battistini, L.,Curti, C.,Rivara, S.,Pala, D.,Kerry, P.S.,Pelosi, G.,Casiraghi, G.,Rassu, G.,Zanardi, F.
Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate.
Org.Biomol.Chem., 12:1561-1569, 2014

PubMed Abstract: A stereodivergent plan is presented leading to all eight stereoisomers of oseltamivir carboxylate (OC). Key chemical manoeuvers are (1) a three-component vinylogous Mukaiyama-Mannich reaction, which sets the whole carbon skeleton and heteroatom substituents, and (2) an intramolecular, silylative Mukaiyama aldol reaction, which creates the targeted carbocycle. The viability of the plan was demonstrated by the first total synthesis of 4-epi-oseltamivir carboxylate (6), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound 6 inhibits influenza A virus strains H1N1 and H3N2 at the μM level, about 150 000-fold less than the OC reference, testifying that the stereodisposition of the C4 acetamido function is key for enzyme recognition. Guided by in-depth structural evaluation including NMR solution studies, molecular mechanics simulations, docking analyses and X-ray crystallography, rationalization of the biological verdict was established.

PubMed: 24425043
DOI: 10.1039/c3ob42069h

実験手法

X-RAY DIFFRACTION (2.1 Å)