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PDBsum entry 3zd0
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Transport protein
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PDB id
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3zd0
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References listed in PDB file
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Key reference
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Title
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Structure-Guided design affirms inhibitors of hepatitis c virus p7 as a viable class of antivirals targeting virion release.
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Authors
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T.L.Foster,
G.S.Thompson,
A.P.Kalverda,
J.Kankanala,
M.Bentham,
L.F.Wetherill,
J.Thompson,
A.M.Barker,
D.Clarke,
M.Noerenberg,
A.R.Pearson,
D.J.Rowlands,
S.W.Homans,
M.Harris,
R.Foster,
S.Griffin.
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Ref.
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Hepatology, 2014,
59,
408-422.
[DOI no: ]
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PubMed id
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Abstract
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Current interferon-based therapy for hepatitis C virus (HCV) infection is
inadequate, prompting a shift toward combinations of direct-acting antivirals
(DAA) with the first protease-targeted drugs licensed in 2012. Many compounds
are in the pipeline yet primarily target only three viral proteins, namely,
NS3/4A protease, NS5B polymerase, and NS5A. With concerns growing over
resistance, broadening the repertoire for DAA targets is a major priority. Here
we describe the complete structure of the HCV p7 protein as a monomeric hairpin,
solved using a novel combination of chemical shift and nuclear Overhauser effect
(NOE)-based methods. This represents atomic resolution information for a
full-length virus-coded ion channel, or "viroporin," whose essential
functions represent a clinically proven class of antiviral target exploited
previously for influenza A virus therapy. Specific drug-protein interactions
validate an allosteric site on the channel periphery and its relevance is
demonstrated by the selection of novel, structurally diverse inhibitory small
molecules with nanomolar potency in culture. Hit compounds represent a
10,000-fold improvement over prototypes, suppress rimantadine resistance
polymorphisms at submicromolar concentrations, and show activity against other
HCV genotypes. Conclusion: This proof-of-principle that structure-guided design
can lead to drug-like molecules affirms p7 as a much-needed new target in the
burgeoning era of HCV DAA. (Hepatology 2014;59:408-422).
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Secondary reference #1
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Title
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Structural and functional characterisation of the hep c virus proteins p7, Ns2-3 and ns5a
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Author
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T.L.Foster.
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Ref.
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ph d thesis ...
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