Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone.
The effects of thiosemicarbazone derivatives of 2-acetylpyridine on mammalian and viral ribonucleoside diphosphate reductases were investigated. The enzymes were partially purified from uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells by sequential salt fractionation with streptomycin sulfate and ammonium sulfate and by affinity chromatography on ATP-agarose. The five thiosemicarbazone derivatives investigated were all potent inhibitors of the virus-induced reductase. Fifty percent inhibitory concentrations (IC50 values) range from 2 to 13 microM. Four of the five derivatives also were inhibitors of the host cell reductase (IC50 values = 7-34 microM). A semicarbazone was inactive against the cellular enzyme and relatively weak as an inhibitor of the viral enzyme (IC50 = 340 microM). Four of six compounds were preferential inhibitors of the viral reductase based on a comparison of IC50 values (5- to greater than 85-fold difference). Kinetic experiments revealed that inhibition of the HSV-1 reductase by the thiosemicarbazones was noncompetitive with respect to CDP and dithiothreitol. A comparison of the inhibitory effects of 2-acetylpyridine thiosemicarbazone itself on viral reductase and on virus replication in vitro demonstrated a similarity in the dose-response relationships for the two parameters. This observation supports the hypothesis that the HSV-induced ribonucleoside diphosphate reductase is an important target for the design of antiviral drugs.
D000998:Antiviral Agents / Q000494:pharmacology*; D003565:Cytidine Diphosphate / Q000494:pharmacology; D004229:Dithiothreitol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007700:Kinetics; D012262:Ribonucleoside Diphosphate Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology*; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D013882:Thiosemicarbazones; D003565:Cytidine Diphosphate; C033836:2-acetylpyridine thiosemicarbazone; D012264:Ribonucleotide Reductases; D012262:Ribonucleoside Diphosphate Reductase; D004229:Dithiothreitol