Structural characterization of the Hepatitis C Virus NS3 protease from genotype 3a: the basis of the genotype 1b vs. 3a inhibitor potency shift

Mariana Gallo; Matthew James Bottomley; Matteo Pennestri; Tommaso Eliseo; Maurizio Paci; Uwe Koch; Renzo Bazzo; Vincenzo Summa; Andrea Carfì; Daniel O Cicero

doi:10.1016/j.virol.2010.05.035

Structural characterization of the Hepatitis C Virus NS3 protease from genotype 3a: the basis of the genotype 1b vs. 3a inhibitor potency shift

Virology. 2010 Sep 30;405(2):424-38. doi: 10.1016/j.virol.2010.05.035. Epub 2010 Jul 13.

Authors

Mariana Gallo¹, Matthew James Bottomley, Matteo Pennestri, Tommaso Eliseo, Maurizio Paci, Uwe Koch, Renzo Bazzo, Vincenzo Summa, Andrea Carfì, Daniel O Cicero

Affiliation

¹ Department of Chemical Science and Technology University of Rome Tor Vergata, Italy.

PMID: 20630554
DOI: 10.1016/j.virol.2010.05.035

Abstract

The first structural characterization of the genotype 3a Hepatitis C Virus NS3 protease is reported, providing insight into the differential susceptibility of 1b and 3a proteases to certain inhibitors. Interaction of the 3a NS3 protease with a P2-P4 macrocyclic and a linear phenethylamide inhibitor was investigated. In addition, the effect of the NS4A cofactor binding on the conformation of the protease was analyzed. Complexation of NS3 with the phenethylamide inhibitor significantly stabilizes the protease but binding does not involve residues 168 and 123, two key amino acids underlying the different inhibition of genotype 1b vs. 3a proteases by P2-P4 macrocycles. Therefore, we studied the dynamic behavior of these two residues in the phenethylamide complex, serving as a model of the situation in the apo 3a protein, in order to explore the structural basis of the inhibition potency shift between the proteases of the genotypes 1b and 3a.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Carrier Proteins / chemistry
Carrier Proteins / metabolism
Genotype
Hepacivirus / classification
Hepacivirus / drug effects
Hepacivirus / enzymology*
Hepacivirus / genetics*
Humans
Intracellular Signaling Peptides and Proteins
Macrocyclic Compounds / chemistry
Macrocyclic Compounds / metabolism
Macrocyclic Compounds / pharmacology*
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Sequence Data
Protease Inhibitors / chemistry
Protease Inhibitors / metabolism
Protease Inhibitors / pharmacology*
Protein Binding
Protein Conformation
Surface Plasmon Resonance
Viral Nonstructural Proteins / antagonists & inhibitors
Viral Nonstructural Proteins / chemistry*
Viral Nonstructural Proteins / genetics
Viral Proteins / chemistry
Viral Proteins / metabolism

Substances

Carrier Proteins
Intracellular Signaling Peptides and Proteins
Macrocyclic Compounds
NS3 protein, hepatitis C virus
NS4A cofactor peptide, Hepatitis C virus
Protease Inhibitors
Viral Nonstructural Proteins
Viral Proteins