Crystal structure of a new benzoic acid inhibitor of influenza neuraminidase bound with a new tilt induced by overpacking subsite C6.

BMC Structural Biology
Lalitha VenkatramaniBlaine H M Mooers

Abstract

Influenza neuraminidase (NA) is an important target for antiviral inhibitors since its active site is highly conserved such that inhibitors can be cross-reactive against multiple types and subtypes of influenza. Here, we discuss the crystal structure of neuraminidase subtype N9 complexed with a new benzoic acid based inhibitor (2) that was designed to add contacts by overpacking one side of the active site pocket. Inhibitor 2 uses benzoic acid to mimic the pyranose ring, a bis-(hydroxymethyl)-substituted 2-pyrrolidinone ring in place of the N-acetyl group of the sialic acid, and a branched aliphatic structure to fill the sialic acid C6 subsite. Inhibitor 2 {4-[2,2-bis(hydroxymethyl)-5-oxo-pyrrolidin-1-yl]-3-[(dipropylamino)methyl)]benzoic acid} was soaked into crystals of neuraminidase of A/tern/Australia/G70c/75 (N9), and the structure refined with 1.55 Å X-ray data. The benzene ring of the inhibitor tilted 8.9° compared to the previous compound (1), and the number of contacts, including hydrogen bonds, increased. However, the IC50 for compound 2 remained in the low micromolar range, likely because one propyl group was disordered. In this high-resolution structure of NA isolated from virus grown in chicken eggs, we found elect...Continue Reading

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Citations

Feb 2, 2013·Expert Opinion on Therapeutic Patents·Supakarn Chamni, Wanchai De-Eknamkul
Aug 7, 2013·Bioorganic & Medicinal Chemistry Letters·Sameer AgarwalHans-Joachim Knölker
Feb 5, 2019·Acta Crystallographica. Section F, Structural Biology Communications·Victor A StreltsovJennifer L McKimm-Breschkin
Nov 13, 2020·Protein Science : a Publication of the Protein Society·Blaine H M Mooers, Marina E Brown

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Methods Mentioned

BETA
X-ray
glycosylation
gel filtration

Software Mentioned

SUPERPOSE
FlexX
HBPLUS
Liglot +
PRODRG
Glycan Builder
PyMOL
REDUCE
SCALA
COOT

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