4A1T: Co-Complex Of The Of Ns3-4a Protease With The Inhibitory Peptide Cp5-46-A (In-House Data)

Citation:
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.
PDB ID: 4A1TDownload
MMDB ID: 103029
PDB Deposition Date: 2011/9/19
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 2.05  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 4A1T: dimeric; determined by author and by software (PISA)
Molecular Components in 4A1T
Label Count Molecule
Proteins (2 molecules)
1
Nonstructural Protein 4A, Serine Protease NS3
Molecule annotation
1
Cp5-46-a Peptide
Molecule annotation
Chemicals (11 molecules)
1
1
2
1
3
5
4
3
5
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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