1887

Abstract

A variant was selected from a clinical isolate of herpes simplex virus type 1 (HSV-1) during a single passage in the presence of a helicase–primase inhibitor (HPI) at eight times the IC. The variant was approximately 40-fold resistant to the HPI BAY 57-1293 and it showed significantly reduced growth in tissue culture with a concomitant reduction in virulence in a murine infection model. The variant contained a single mutation (Asn342Lys) in the UL5 predicted functional helicase motif IV. The Asn342Lys mutation was transferred to a laboratory strain, PDK cl-1, and the recombinant acquired the expected resistance and reduced growth characteristics. Comparative modelling and docking studies predicted the Asn342 position to be physically distant from the HPI interaction pocket formed by UL5 and UL52 (primase). We suggest that this mutation results in steric/allosteric modification of the HPI-binding pocket, conferring an indirect resistance to the HPI. Slower growth and moderately reduced virulence suggest that this mutation might also interfere with the helicase–primase activity.

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2009-08-01
2019-11-22
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Supplements

vol. , part 8, pp. 1937 - 1942

The atomic co-ordinates of the predicted HSV-1 UL5–BAY 57-1293 complex are available to download here(PDB file; 399 KB). Please right-click and save the file. This can then be viewed by using Jmol, an open-source Java viewer for chemical structures in 3D.

These data can also be viewed by downloading the file from the following page: http://torsa.bioc.cam.ac.uk/~ricardo/PDBs/hsH-BAY_57-1293.pdb.



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