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PDBsum entry 1l7h
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Structural studies of the resistance of influenza virus neuramindase to inhibitors.
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Authors
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B.J.Smith,
J.L.Mckimm-Breshkin,
M.Mcdonald,
R.T.Fernley,
J.N.Varghese,
P.M.Colman.
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Ref.
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J Med Chem, 2002,
45,
2207-2212.
[DOI no: ]
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PubMed id
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Abstract
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Zanamivir and oseltamivir, specific inhibitors of influenza virus neuraminidase,
have significantly different characteristics in resistance studies. In both
cases resistance is known to arise through mutations in either the hemagglutinin
or neuraminidase surface proteins. A new inhibitor under development by Biocryst
Pharmaceuticals, BCX-1812, has both a guanidino group, as in zanamivir, and a
bulky hydrophobic group, as in oseltamivir. Using influenza
A/NWS/Tern/Australia/G70C/75 (H1N9), neuraminidase variants E119G and R292K have
previously been selected by different inhibitors. The sensitivity of these
variants to BCX-1812 has now been measured and found in both cases to be
intermediate between those of zanamivir and oseltamivir. In addition, the X-ray
crystal structures of the complexes of BCX-1812 with the wild type and the two
mutant neuraminidases were determined. The ligand is bound in an identical
manner in each structure, with a rearrangement of the side chain of E276 from
its ligand-free position. A structural explanation of the mechanism of
resistance of BCX-1812, relative to zanamivir and oseltamivir in particular, is
provided.
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Secondary reference #1
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Title
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Drug design against a shifting target: a structural basis for resistance to inhibitors in a variant of influenza virus neuraminidase.
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Authors
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J.N.Varghese,
P.W.Smith,
S.L.Sollis,
T.J.Blick,
A.Sahasrabudhe,
J.L.Mckimm-Breschkin,
P.M.Colman.
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Ref.
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Structure, 1998,
6,
735-746.
[DOI no: ]
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PubMed id
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Figure 1.
Figure 1. The chemical structures of influenza
neuraminidase inhibitors: 1, sialic acid (N-acetylneuraminic
acid (Neu5Ac)); 2, 2-deoxy-2,3-dehydro-N-acetylneuraminic acid
(Neu5Ac2en); 3, 4-amino-Neu5Ac2en; 4, Zanamivir,
4-guanidino-Neu5Ac2en; 5,
5-N-acetyl-4-guanidino-6-methyl(propyl)
carboxamide-4,5-dihydro-2H-pyran-2-carboxylic acid; 6,
5-N-acetyl-4-amino-6-diethyl
carboxamide-4,5-dihydro-2H-pyran-2-carboxylic acid; and 7,
GS4071,
4-N-acetyl-5-amino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylic
acid.
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The above figure is
reproduced from the cited reference
with permission from Cell Press
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