Regulatory effects of deoxyribonucleosides on the activity of 5-methoxymethyl-2'-deoxycytidine: modulation of antiherpes activity by deoxyguanosine and tetrahydrodeoxyuridine.
The effect of purine and pyrimidine deoxyribonucleosides on the activity of 5-methoxymethyl-2'-deoxycytidine (MMdCyd) against herpes simplex virus type 1 (HSV-1) was investigated. The antiviral activity of MMdCyd was decreased by deoxythymidine, deoxyuridine and deoxycytidine. Deoxyadenosine had no effect at concentrations up to 500 microM. In contrast, deoxyguanosine (dGuo) potentiated MMdCyd activity. The mean ED50 (1.5 microM) for the combination (MMdCyd plus 100 microM dGuo) was approximately 20-fold lower than that of MMdCyd (ED50 26 microM). When tetrahydrodeoxyuridine (H4dUrd, 540 microM) was added along with MMdCyd and dGuo, anti-HSV-1 activity of MMdCyd was further potentiated by 25-fold (ED50 0.06 microM). The inhibition of virus replication, as determined by the plaque reduction assay, was further confirmed by virus yield studies and by parallel observations on virus-induced cytopathogenicity. The order of decreasing effectiveness for reducing the production of infectious virus particles (virus yield) by different treatments was: MMdCyd + dGuo + H4dUrd greater than MMdCyd + DGuo greater than MMdCyd + H4dUrd greater than MMdCyd greater than dGuo + H4dUrd greater than dGuo greater than H4dUrd. The effect of dGuo and dGuo in combination with H4dUrd on deoxyribonucleoside triphosphate (dNTP) pools was determined in Vero cells infected with multiplicity of infection of 5 PFU/cell. In the presence of 100 microM dGuo, there was approximately a 3-fold, 2-fold and 12-fold increase in dCTP, dTTP and dGTP pool sizes respectively, as compared to control (untreated) cells. Treatment with H4dUrd (1.06 mM) in combination with dGuo (100 microM), resulted in an increase of the dCTP pool and a marked fall in the dTTP and dGTP pool. The possible mechanisms for potentiation of MMdCyd activity by dGuo and H4dUrd are discussed.
Aduma
P J
PJ
Department of Physiological Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Canada.
Gupta
S V
SV
Stuart
A L
AL
Tourigny
G
G
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology* / Q000633:toxicity; D003844:DCMP Deaminase / Q000037:antagonists & inhibitors*; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000378:metabolism; D003849:Deoxyguanosine / Q000494:pharmacology* / Q000633:toxicity; D003853:Deoxyribonucleosides / Q000494:pharmacology*; D018139:Simplexvirus / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D013767:Tetrahydrouridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014709:Vero Cells
D000998:Antiviral Agents; D003853:Deoxyribonucleosides; D003841:Deoxycytidine; C071169:5-methoxymethyl-2-deoxycytidine; D013767:Tetrahydrouridine; C052729:2'-deoxytetrahydrouridine; D003844:DCMP Deaminase; D003849:Deoxyguanosine