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PDBsum entry 4a1v
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Hydrolase/peptide
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PDB id
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4a1v
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References listed in PDB file
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Key reference
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Title
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High affinity peptide inhibitors of the hepatitis c virus ns3-4a protease refractory to common resistant mutants.
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Authors
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J.Kügler,
S.Schmelz,
J.Gentzsch,
S.Haid,
E.Pollmann,
J.Van den heuvel,
R.Franke,
T.Pietschmann,
D.W.Heinz,
J.Collins.
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Ref.
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J Biol Chem, 2012,
287,
39224-39232.
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PubMed id
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Abstract
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Hepatitis C virus (HCV) NS3-4A protease is essential for viral replication. All
current small molecular weight drugs against NS3-4A are substrate
peptidomimetics that have a similar binding and resistance profile. We developed
inhibitory peptides (IPs) capping the active site and binding via a novel
"tyrosine" finger at an alternative NS3-4A site that is of particular
interest for further HCV drug development. The peptides are not cleaved due to a
combination of geometrical constraints and impairment of the oxyanion hole
function. Selection and optimization through combinatorial phagemid display,
protein crystallography, and further modifications resulted in a 32-amino acid
peptide with a K(i) of 0.53 nm. Inhibition of viral replication in cell culture
was demonstrated by fusion to a cell-penetrating peptide. Negligible
susceptibility to known (A156V and R155K) resistance mutations of the NS3-4A
protease was observed. This work shows for the first time that antiviral
peptides can target an intracellular site and reveals a novel druggable site on
the HCV protease.
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