We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

4m3m

From Proteopedia

Jump to: navigation, search

Influenza Neuraminidase in complex with a stereomutated analogue of Oseltamivir carboxylate

Structural highlights

4m3m is a 1 chain structure with sequence from Influenza A virus (A/duck/Ukraine/1/1963(H3N8)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NRAM_I63A3 Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moities on the mucin of the airway epithelial cells. Likely to plays a role in the budding process through its association with lipid rafts during intracellular transport. May additionally display a raft-association independent effect on budding. Plays a role in the determination of host range restriction on replication and virulence. Sialidase activity in late endosome/lysosome traffic seems to enhance virus replication.

Publication Abstract from PubMed

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 (), accessed in 15 steps from glyceraldehyde, o-anisidine and pyrrole siloxydiene precursors. Compound inhibits influenza A virus strains H1N1 and H3N2 at the muM 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.

Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate.,Sartori A, Dell'amico L, Battistini L, Curti C, Rivara S, Pala D, Kerry PS, Pelosi G, Casiraghi G, Rassu G, Zanardi F Org Biomol Chem. 2014 Feb 11;12(10):1561-9. doi: 10.1039/c3ob42069h. PMID:24425043^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sartori A, Dell'amico L, Battistini L, Curti C, Rivara S, Pala D, Kerry PS, Pelosi G, Casiraghi G, Rassu G, Zanardi F. Synthesis, structure and inhibitory activity of a stereoisomer of oseltamivir carboxylate. Org Biomol Chem. 2014 Feb 11;12(10):1561-9. doi: 10.1039/c3ob42069h. PMID:24425043 doi:http://dx.doi.org/10.1039/c3ob42069h