2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U), a potent inactivator of ribonucleotide reductases of herpes simplex and varicella-zoster viruses and a potentiator of acyclovir.
2-Acetylpyridine 5-[(dimethylamino)thiocarbonyl]thiocarbonohydrazone (A1110U) was found to be a potent inactivator of the ribonucleotide reductases (EC 1.17.4.1) encoded by herpes simplex virus types 1 and 2 and by varicella-zoster virus and to be a weaker inactivator of human ribonucleotide reductase. It also markedly potentiated the antiherpetic activity of acyclovir against these viruses in tissue culture. A1110U both decreased the dGTP pool that builds up when infected cells are treated with acyclovir and induced a large increase in the pool of acyclovir triphosphate. The resultant 100-fold increase in the ratio of the concentrations of acyclovir triphosphate to dGTP should facilitate the binding of the fraudulent nucleotide to its target enzyme, herpes virus-encoded DNA polymerase, and could account for the synergy between A1110U and acyclovir. A similar change in the acyclovir triphosphate-to-dGTP ratio was previously reported to be induced by another ribonucleotide reductase inhibitor, 2-acetylpyridine 4-(2-morpholinoethyl)thiosemicarbazone (A723U). However, A1110U is considerably more potent and may have better clinical potential. Synergistic toxic interactions between A1110U and acyclovir were not detected in uninfected cells.
Spector
T
T
Division of Experimental Therapy, Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Harrington
J A
JA
Morrison
R W
RW
Lambe
C U
CU
Nelson
D J
DJ
Averett
D R
DR
Biron
K
K
Furman
P A
PA
D000212:Acyclovir / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D004357:Drug Synergism; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology*; D007700:Kinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D006835:Hydrazones; D011725:Pyridines; C059415:A 1110U; D012264:Ribonucleotide Reductases; D000212:Acyclovir