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

Biswas, Subhajit and Kleymann, Gerald and Swift, Mihaiela and Tiley, Laurence S. and Lyall, Jonathan and Aguirre-Hernández, Jesús and Field, Hugh J. (2008) 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. Journal of Antimicrobial Chemotherapy, 61 (5). pp. 1044-1047. ISSN 0305-7453

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Official URL: http://jac.oxfordjournals.org/content/61/5/1044.lo...

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 ID50 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.

Item Type:Article
Keywords:herpes simplex virus, BAY 57-1293, BILS 22 BS, mutation
Subjects:C Biological Sciences > C540 Virology
A Medicine and Dentistry > A300 Clinical Medicine
C Biological Sciences > C521 Medical Microbiology
F Physical Sciences > F151 Pharmaceutical Chemistry
Divisions:College of Science > School of Life Sciences
ID Code:6962
Deposited By:INVALID USER
Deposited On:26 Nov 2012 17:50
Last Modified:21 Jul 2014 08:48

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