Herpes and human ribonucleotide reductases. Inhibition by 2-acetylpyridine 5-[(2-chloroanilino)-thiocarbonyl]-thiocarbonohydrazone (348U87).
The mode of inactivation of herpes simplex virus type 1 and human ribonucleotide reductases by 2-acetylpyridine 5-[(2-chloroanilino)-thiocarbonyl]-thiocarbonohydrazone++ + (348U87) was determined and compared to that described previously [Porter et al. Biochem Pharmacol 39: 639-646, 1990] for 2-acetylpyridine 5-[(dimethylamino)thiocarbonyl]-thiocarbonohydrazone (A1110U). 348U87 inactivated herpes ribonucleotide reductase faster than did A1110U. Moreover, iron-complexed 348U87 was a considerably more potent inactivator than iron-complexed A1110U. It appeared to efficiently form an initial complex with the viral enzyme prior to rapid enzyme inactivation. The combination of 348U87 and iron-complexed 348U87 inactivated with a rate constant that was slightly greater than the sum of their individual rate constants of inactivation. The corresponding combination of A1110U species inactivated with a rate constant that was much greater than the sum of the individual rate constants of inactivation. Herpes ribonucleotide reductase that had been inactivated by either species of 348U87 was reactivated by diluting the enzyme and inactivators into assay medium containing excess iron. 348U87 was also an effective inactivator of herpes simplex virus type 2 and varicella zoster virus ribonucleotide reductases. The iron-complexed forms of 348U87 and A1110U exhibited very different modes of inactivation of human ribonucleotide reductase. Iron-complexed 348U87 was a tight-binding inactivator, whereas iron-complexed A1110U was only a weak, non-inactivating, inhibitor. Furthermore, the inactivation by iron-complexed 348U87 was not stimulated by either 348U87 or A1110U, whereas the weak inhibition by iron-complexed A1110U was converted to rapid inactivation by A1110U. Excess iron prevented the inactivation by iron-complexed 348U87. Uncomplexed 348U87 was similar to uncomplexed A1110U in that it was not an inhibitor of the human enzyme.
Spector
T
T
Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Harrington
J A
JA
Porter
D J
DJ
D000998:Antiviral Agents; D002614:Chelating Agents; D004347:Drug Interactions; D004793:Enzyme Reactivators; D014645:Herpesvirus 3, Human / Q000201:enzymology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000494:pharmacology*; D007501:Iron; D007700:Kinetics; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000187:drug effects / Q000201:enzymology*
D000998:Antiviral Agents; D002614:Chelating Agents; D004793:Enzyme Reactivators; D006835:Hydrazones; D011725:Pyridines; C069703:compound 348U87; C059415:A 1110U; D007501:Iron; D012264:Ribonucleotide Reductases