Alterations in the Recognition of Nucleoside Analogues as Substrates by the Deoxythymidine Kinase of a 5-Methoxymethyldeoxyuridine-resistant Mutant of Herpes Simplex Virus Type 1

• Published in: Journal of general virology 1983-12, Vol.64 (12), p.2767-2770
• Main Authors: Veerisetty, V, Veerisetty, Indira K, Gentry, Glenn A
• Format: Article
• Language: English
• Subjects: Action of physical and chemical agents; Binding Sites; Biological and medical sciences; Deoxyuridine - analogs & derivatives; Deoxyuridine - pharmacology; Drug Resistance, Microbial; Fundamental and applied biological sciences. Psychology; herpes simplex virus 1; Kinetics; Microbiology; Mutation; Nucleosides - metabolism; Simplexvirus - drug effects; Simplexvirus - enzymology; Simplexvirus - genetics; Structure-Activity Relationship; Substrate Specificity; Thymidine Kinase - metabolism; Thymine Nucleotides - pharmacology; Virology
• ISSN: 0022-1317; 1465-2099
• DOI: 10.1099/0022-1317-64-12-2767

Department of Microbiology and 1 Department of Medicine, University of Mississippi Medical Center, School of Medicine, Jackson, Mississippi 39216, U.S.A. Inhibition constants ( K i s) were used as an estimate of the ability of various nucleoside analogues to be recognized as substrates by the deoxythymidine kinases (dTKs) of a 5-methoxymethyldeoxyuridine-resistant (MMdU r ) mutant of herpes simplex virus type 1 (HSV-1) and its parent wild-type (wt). It was found that the K i s for the 5-position analogues MMdU, [ E ]-5-(2-bromovinyl)deoxyuridine, bromodeoxyuridine and iododeoxyuridine were increased approximately three-to fivefold, suggesting that they were poorer substrates for the MMdU r dTK than for the wt dTK. With the 2' analogues arabinosylthymine and 2' fluoro 5-methylarabinosyluracil, however, the K i s were increased to a much greater extent, 80- and 240-fold, respectively. These findings suggest that the resistance of the mutant MMdU r to these analogues may be due to a mutation(s) in the viral dTK that directly affects binding at the 2' recognition site and indirectly at the 5, while still allowing substantial activity with the natural substrate deoxythymidine. Keywords: HSV-1 dTKs, nucleoside analogues, drug resistance Received 18 May 1983; accepted 17 August 1983.