Thymidine kinase from herpes simplex

Panicali, D., and Paoletti, E. (1982) Construction of poxviruses as cloning vectors Insertion of the thymidine kinase from herpes simplex virus into the DNA of infectious vaccinia virus. Proc. Natl. Acad. Sci. USA 79, 4927-4931. 

M. Keller, P. A. Furman, R. L. Miller and G. B. Elion, Thymidine kinase from herpes simplex virus phosphorylates the new antiviral compound, 9-(2-hydroxy-ethoxymethy1)guanine, J. Biol. Chem. 253 8721 (1978). 

Treatment of adenosine with sodium toluene-p-sulphinate and sodium hypochlorite gives a 50% yield of 2 -0-tosyladenosine. iV-Chloro intermediates are thought to be involved, which then give tosyl chloride by reaction with the sulphinate, but it is unclear why this procedure gives a higher yield than direct tosylation.229 Amino acids linked to (deoxy)-nucleosides via a sulphamoyl group have been reported they are structurally similar to the antibiotic ascamycin (see also Vol. 23, p.226).230 3. and 5 -0-dansyl derivatives of thymidine have been prepared, and shown to act as inhibitors of thymidine kinase from herpes simplex virus.231... 

BVdU differs from IdU and F TdU by being specifically phosphorylated in the 5 -position by herpes simplex vims type-1 (HSV-1) induced thymidine kinase. This restricts its action to cells infected by HSV-1. It is less active against genital herpes (HSV-2). HSV-l-induced thymidine kinase converts BVdU to the corresponding 5 -mono- and diphosphate, but HSV-2-induced thymidine kinase stops at the stage of the 5 -phosphate of BVdU. Apparendy, cellular kinases phosphorylate BVdU-5 -diphosphate to the corresponding 5 -triphosphate, which inhibits HSV-1 DNA polymerase to a greater extent than similar cellular DNA polymerases. 

Penciclovir [pen SIK lo veer] is an acyclic guanosine nucleoside derivative that is active against herpes simplex virus Types I and II, and against varicella-zoster virus. Penciclovir is only administered topically (Figure 37.8). Penciclovir is monophosphorylated by viral thymidine kinase, and cellular enzymes form the nucleoside triphosphate, which inhibits herpes DNA polymerase. Penciclovir triphosphate has an intracellular half-life 20 to 30 times longer than does acyclovir triphosphate (see p. 365). Penciclovir is negligibly absorbed from topical application, and is well tolerated. Both healing and pain are shortened approximately one-half day in duration, compared to placebo-treated subjects. 

M. oleifera extracts inhibits plaque formation of anti-herpes simplex vims type 1 (HSV-1) more than 50% at 100 ag/ml in a plaque reduction assay (55). M. oleifera extracts are also effective against thymidine kinase-deficient HSV-1 and phosphonoacetate-resistant HSV-1 vims strains. The extract ofM. oleifera at a dose of 750 mg/kg body weight per day significantly delays the development of skin lesions, prolongs the mean survival times and reduces the mortality of HSV-1 infected mice. Compared to the synthetic compound acyclovir, M. oleifera extracts delay the development of skin lesions and has mean survival times as acyclovir. A polysaccharide from hot aqueous extract of mature pods (fruits) of M oleifera with a structural repeating unit [->4)-a-D-GlCp(l->] has immunoenhancing properties (76). 

SELECTIVITY OF ANTIVIRAL EFFECTIVENESS DERIVED FROM DIFFERENCES OF HERPES SIMPLEX VIRUS-CODED THYMIDINE KINASES... 

Figure 8.10 (A) Relationship between the lung uptake of [ F]-FHBG and in vitro enzyme activity of a mutant HSVl-TK. Data are were combined from two studies and were fitted to a hyperbolic equation and corresponding regression curve and are displayed. (B) Relationship between the lung uptake of [ F]-FHBG and mutant HSVl-TK enzyme activity in rats with ANTU-induced increases in pulmonary vascular permeability. [1 F]-FHBG = 9-(4-[ F]-fluoro-3-hydroxymethylbutyl)guanine, ID = injected dose, mHSVl-TK = mutant Herpes simplex virus-1 thymidine kinase, PCV = penciclovir. [Reproduced with permission from Richard et al. (71).]...

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