A mutation in helicase motif IV of herpes simplex virus type 1 UL5 that results in reduced growth in vitro and lower virulence in a murine infection model is related to the predicted helicase structure.

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(50). 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.
Authors	Subhajit Biswas, Ricardo Núñez Miguel, Soumi Sukla, Hugh J Field
Journal	The Journal of general virology (J Gen Virol) Vol. 90 Issue Pt 8 Pg. 1937-1942 (Aug 2009) ISSN: 0022-1317 [Print] England
PMID	19403757 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Antiviral Agents Pyridines Sulfonamides Thiazoles Viral Proteins Virulence Factors pritelivir DNA Primase helicase-primase, Human herpesvirus 1 DNA Helicases
Topics	Amino Acid Substitution (genetics) Animals Antiviral Agents (pharmacology) DNA Helicases (chemistry, genetics, physiology) DNA Primase (chemistry, genetics, physiology) Drug Resistance, Viral Herpesvirus 1, Human (genetics, growth & development, pathogenicity) Mice Models, Molecular Mutation, Missense Pyridines (pharmacology) Sulfonamides Thiazoles (pharmacology) Viral Proteins (chemistry, genetics, physiology) Virulence Virulence Factors (chemistry, genetics, physiology)

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