PDBsum entry 4mjv

Hydrolase/hydrolase inhibitor

PDB id: 4mjv

Contents

Protein chain

390 a.a.

Ligands

27V

Metals

_CA

Waters ×161

PDB id:

4mjv

Name:

Hydrolase/hydrolase inhibitor

Title:

Influenza neuraminidase in complex with a novel antiviral compound

Structure:

Neuraminidase. Chain: a. Ec: 3.2.1.18

Source:

Influenza a virus. Organism_taxid: 385580. Strain: a/duck/ukraine/1/1963 (h3n8)

Resolution:

2.65Å R-factor: 0.209 R-free: 0.285

Authors:

P.S.Kerry

Key ref:

S.Mohan et al. (2014). Serendipitous discovery of a potent influenza virus a neuraminidase inhibitor. Angew Chem Int Ed Engl, 53, 1076-1080. PubMed id: 24339250 DOI: 10.1002/anie.201308142

Date:

04-Sep-13 Release date: 15-Jan-14

Protein chain

Q07599  (NRAM_I63A3) -  Neuraminidase from Influenza A virus (strain A/Duck/Ukraine/1/1963 H3N8)

Seq: 470 a.a.

Struc: 390 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.2.1.18 - exo-alpha-sialidase.
• Reaction: Hydrolysis of alpha-(2->3)-, alpha-(2->6)-, alpha-(2->8)-glycosidic linkages of terminal sialic residues in oligosaccharides, glycoproteins, glycolipids, colominic acid and synthetic substrates.

DOI no: 10.1002/anie.201308142

Angew Chem Int Ed Engl 53:1076-1080 (2014)

PubMed id: 24339250

Serendipitous discovery of a potent influenza virus a neuraminidase inhibitor.

S.Mohan, P.S.Kerry, N.Bance, M.Niikura, B.M.Pinto.

ABSTRACT

We have previously reported a potent neuraminidase inhibitor that comprises a carbocyclic analogue of zanamivir in which the hydrophilic glycerol side chain is replaced by the hydrophobic 3-pentyloxy group of oseltamivir. This hybrid inhibitor showed excellent inhibitory properties in the neuraminidase inhibition assay (Ki =0.46 nM; Ki (zanamivir) =0.16 nM) and in the viral replication inhibition assay in cell culture at 10(-8)  M. As part of this lead optimization, we now report a novel spirolactam that shows comparable inhibitory activity in the cell culture assay to that of our lead compound at 10(-7)  M. The compound was discovered serendipitously during the attempted synthesis of the isothiourea derivative of the original candidate. The X-ray crystal structure of the spirolactam in complex with the N8 subtype neuraminidase offers insight into the mode of inhibition.