Inhibition of herpes simplex virus-induced DNA polymerases and cellular DNA polymerase alpha by triphosphates of acyclic guanosine analogs.

Abstract:

The triphosphates of the antiherpes acyclic guanosine analogs (R)- and (S)-enantiomers of 9-(3,4-dihydroxybutyl)guanine [BCVTP and (S)-DHBGTP], 9-(4-hydroxybutyl)guanine (HBGTP), and 9-(2-hydroxyethoxymethyl)guanine (ACVTP) were investigated for their effects on partially purified DNA polymerases of herpes simplex virus type 1 and type 2 (HSV-1 and HSV-2) as well as cellular DNA polymerase alpha of calf thymus and Vero cells. The triphosphates of the four analogs were all competitive inhibitors when dGTP was the variable substrate with both the viral and the cellular DNA polymerases with activated calf thymus DNA or poly(dC)oligo(dG)12-18 as template. No inhibition was observed with deoxythymidine 5'-triphosphate as substrate and poly(dA)oligo(dT)12-18 as template. All analogs were preferential inhibitors of the viral DNA polymerases. Ordering the compounds according to their decreasing binding affinities, as reflected by their increasing inhibition constants for the viral DNA polymerases, gave ACVTP greater than HBGTP greater than BCVTP greater than (S)-DHBGTP. The DNA polymerase from the HSV-1 mutant, CI(101)P2C5, resistant to ACV, showed a stronger decrease in sensitivity for ACVTP and HBGTP than for BCVTP compared to the effects on DNA polymerase from the wild-type strain CI(101). The analogs were not able to support DNA synthesis in the absence of the competing substrate dGTP. A decrease in the ability of calf thymus DNA to serve as primer template for HSV-2 DNA polymerase was observed after preincubation with the triphosphates of the acyclic guanosine analogs. The analogs showed a progressive inhibition of the HSV-2 DNA polymerase activity with incubation time, and the inhibition could be reversed by high concentrations of dGTP both with and without addition of fresh enzyme or fresh template. However, no reversion was obtained when fresh enzyme or template was added if dGTP was omitted. The data indicate that these analogs inhibited the DNA polymerases by a similar mechanism and that the inhibition was reversible.

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