Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors.
CONTEXT
Natural strain variation and rapid resistance development makes development of broad spectrum hepatitis C virus (HCV) drugs very challenging and evaluation of inhibitor selectivity and resistance must account for differences in the catalytic properties of enzyme variants.


OBJECTIVE
To understand how to study selectivity and relationships between efficacy and genotype or resistant mutants for NS3 protease inhibitors.


MATERIALS AND METHODS
The catalytic properties of NS3 protease from genotypes 1a, 1b and 3a, and their sensitivities to four structurally and mechanistically different NS3 protease inhibitors have been analysed under different experimental conditions.


RESULTS
The optimisation of buffer conditions for each protease variant enabled the comparison of their catalytic properties and sensitivities to the inhibitors. All inhibitors were most effective against genotype 1a protease, with VX-950 having the broadest selectivity.


DISCUSSION AND CONCLUSION
A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.
['Ehrenberg|Angelica E|AE|', 'Schmuck|Benjamin|B|', 'Anwar|Muhammad Ikram|MI|', 'Gustafsson|Sofia Svahn|SS|', 'Stenberg|Gun|G|', 'Danielson|U Helena|UH|']
D000998:Antiviral Agents D002219:Carbamates D003001:Cloning, Molecular D003521:Cyclopropanes D024882:Drug Resistance, Viral D004926:Escherichia coli D015870:Gene Expression D014644:Genetic Variation D005838:Genotype D016174:Hepacivirus D054833:Isoindoles D007769:Lactams D047029:Lactams, Macrocyclic D047028:Macrocyclic Compounds D009154:Mutation D009842:Oligopeptides D011392:Proline D011480:Protease Inhibitors D017434:Protein Structure, Tertiary D011804:Quinolines D011994:Recombinant Proteins D013449:Sulfonamides D013844:Thiazoles D017361:Viral Nonstructural Proteins
HCV Experimental conditions inhibition optimization vitality value