3ZD0: The Solution Structure of Monomeric Hepatitis C Virus p7 Yields Potent Inhibitors of Virion Release

Citation:
Abstract
UNLABELLED: 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.
PDB ID: 3ZD0Download
MMDB ID: 113136
PDB Deposition Date: 2010
Updated in MMDB: 2013/09
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 3ZD0: monomeric; determined by software (PISA)
Molecular Components in 3ZD0
Label Count Molecule
Protein (1 molecule)
1
P7 Protein
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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