A single drug-resistance mutation in HSV-1 UL52 primase points to a difference between two helicase-primase inhibitors in their mode of interaction with the antiviral target.
J Antimicrob Chemother
; 61(5): 1044-7, 2008 May.
Article
en En
| MEDLINE
| ID: mdl-18299638
ABSTRACT
OBJECTIVES:
To investigate the mechanism of action of the helicase-primase inhibitors (HPIs) BAY 57-1293 and BILS 22 BS by selection and characterization of drug-resistant herpes simplex virus (HSV)-1 mutants.METHODS:
HSV-1 mutants were selected using BAY 57-1293 in Vero cells. Resistance mutations identified in the UL5 helicase or UL52 primase genes were validated by marker transfer. Cross-resistance to the structurally distinct BILS 22 BS was measured by ID(50) determinations.RESULTS:
(i) A single mutation (UL52 A899T) confers 43-fold resistance to BAY 57-1293, but does not confer any resistance to BILS 22 BS. (ii) A double mutant (UL52 A899T and UL5 K356T) is 2500-fold resistant to BAY 57-1293, which is more than 17 times the sum of fold-resistance due to the individual mutations, UL52 A899T (43-fold) and UL5 K356T (100-fold). (iii) Virus containing the single helicase mutation and the double mutant with mutations in both helicase and primase showed equal resistance to BILS 22 BS (70-fold).CONCLUSIONS:
By measuring the relative inhibitory concentrations required to overcome particular mutations in the helicase and primase proteins, evidence was obtained that BAY 57-1293 interacts with both components of the helicase-primase complex to achieve maximum potency, whereas for BILS 22BS, this may not be the case. Furthermore, our observations suggest that BAY 57-1293 interacts simultaneously with UL5 and UL52. Overall, the results suggest that these two potent HPIs interact differently with the helicase-primase complex.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Antivirales
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Piridinas
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Tiazoles
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Proteínas Virales
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Herpesvirus Humano 1
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ADN Helicasas
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ADN Primasa
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Farmacorresistencia Viral
Idioma:
En
Revista:
J Antimicrob Chemother
Año:
2008
Tipo del documento:
Article
País de afiliación:
Reino Unido