4A1T

Co-Complex of the of NS3-4A protease with the inhibitory peptide CP5- 46-A (in-House data)

Summary for 4A1T

• Entry DOI: 10.2210/pdb4a1t/pdb
• Related: 1DXP 1DY9 1W3C 4A1V 4A1X
• Descriptor: NONSTRUCTURAL PROTEIN 4A, SERINE PROTEASE NS3, CP5-46-A PEPTIDE, BICARBONATE ION, ... (9 entities in total)
• Functional Keywords: hydrolase-peptide complex, unmodified inhibitory peptides, hydrolase/peptide
• Biological source: HEPATITIS C VIRUS; More
• Total number of polymer chains: 4
• Total formula weight: 48477.84

Authors

Schmelz, S.,Kuegler, J.,Collins, J.,Heinz, D.W. (deposition date: 2011-09-19, release date: 2012-09-19, Last modification date: 2024-11-20)

Primary citation

Kugler, J.,Schmelz, S.,Gentzsch, J.,Haid, S.,Pollmann, E.,Van Den Heuvel, J.,Franke, R.,Pietschmann, T.,Heinz, D.W.,Collins, J.
High Affinity Peptide Inhibitors of the Hepatitis C Virus Ns3-4A Protease Refractory to Common Resistant Mutants.
J.Biol.Chem., 287:39224-, 2012

PubMed Abstract: 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.

PubMed: 22965230
DOI: 10.1074/JBC.M112.393843

Experimental method

X-RAY DIFFRACTION (2.05 Å)