Potentiation of antiherpetic activity of acyclovir by ribonucleotide reductase inhibition.
Compound A723U, a 2-acetylpyridine thiosemicarbazone, produced apparent inactivation of herpes simplex virus type 1 (HSV-1) ribonucleotide reductase. Inactivation occurred after A723U formed a reversible complex with the enzyme and only while the enzyme was catalyzing the formation of deoxynucleotides. A723U inhibited HSV-1 replication at concentrations that were not toxic to the confluent host cells. Most importantly, A723U and acyclovir (ACV) were found to exhibit mutual potentiation of their antiviral activities. Subinhibitory concentrations of either compound greatly reduced the ED50 (median effective dose) of the other. Studies of the deoxynucleotide pool sizes and the levels of ACV triphosphate (ACV-P3) revealed that A723U not only significantly reduced the pool of dGTP but also increased the level of ACV-P3 in infected cells. The net result was an 80-fold increase in the ratio of ACV-P3 to dGTP. This should greatly facilitate the initial binding of ACV-P3 to HSV-1 DNA polymerase and probably accounts for the mechanism of potentiation.
Spector
T
T
Averett
D R
DR
Nelson
D J
DJ
Lambe
C U
CU
Morrison
R W
RW
St Clair
M H
MH
Furman
P A
PA
D000212:Acyclovir / Q000494:pharmacology*; D003854:Deoxyribonucleotides / Q000378:metabolism; D004357:Drug Synergism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects* / Q000201:enzymology; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D003854:Deoxyribonucleotides; D011725:Pyridines; D013882:Thiosemicarbazones; C045577:compound A723U; D012264:Ribonucleotide Reductases; D000212:Acyclovir