4M3M

Influenza Neuraminidase in complex with a stereomutated analogue of Oseltamivir carboxylate

Summary for 4M3M

• Entry DOI: 10.2210/pdb4m3m/pdb
• Descriptor: Neuraminidase, (3R,4S,5S)-4-(acetylamino)-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylic acid, CALCIUM ION, ... (5 entities in total)
• Functional Keywords: sialidase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Influenza A virus
• Cellular location: Host apical cell membrane ; Single-pass type II membrane protein : Q0A480
• Total number of polymer chains: 1
• Total formula weight: 43668.16

Authors

Kerry, P.S. (deposition date: 2013-08-06, release date: 2014-02-12, Last modification date: 2020-07-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.1 Å)