title: Accounting for strain variations and resistance mutations in the characterization of hepatitis C NS3 protease inhibitors.
abstract: BACKGROUND
  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.
  
  
  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.
  
  
  CONCLUSIONS
  A new strategy for evaluation of inhibitors relevant for the discovery of broad spectrum HCV drugs was established.
authors: Department of Chemistry -- BMC, Uppsala University , Uppsala , Sweden and.
authors: Angelica E
authors: AE
authors: Ehrenberg
authors: Benjamin
authors: B
authors: Schmuck
authors: Muhammad Ikram
authors: MI
authors: Anwar
authors: Sofia Svahn
authors: SS
authors: Gustafsson
authors: Gun
authors: G
authors: Stenberg
authors: U Helena
authors: UH
authors: Danielson
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D003001:Cloning, Molecular; D003521:Cyclopropanes; D024882:Drug Resistance, Viral / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D014644:Genetic Variation; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D054833:Isoindoles; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D009842:Oligopeptides; D011392:Proline; D011480:Protease Inhibitors; D011804:Quinolines; D011994:Recombinant Proteins; D013449:Sulfonamides; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; C479555:BILN 2061; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C486464:telaprevir; C553752:danoprevir
keywords: Experimental conditions; HCV; inhibition; optimization; vitality value