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1、Vol. 36, 1992POTENTIATORS OF ACYCLOVIR 937Antimicrobial Agents and Chemotherapy, May 1992, p. 934-9370066-4804/92/050934-04$02.00/0Copyright 1992, American Society for MicrobiologyInactivators of Herpes Simplex Virus Ribonucleotide Reductase:Hematological Profiles and In Vivo Potentiationof the Anti
2、viral Activity of AcyclovirTHOMAS SPECTOR,1* DAVID C. LOBE,2 M. NIXON ELLIS,2 TODD A. BLUMENKOPF,3and GEORGE M. SZCZECH4Divisions of Experimental Therapy,1 Virology,2 Organic Chemistry,3 and Toxicology and Pathology,4Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709Receive
3、d 12 November 1991/Accepted 21 January 1992A1110U (BW 1110U81) is an inactivator of herpesvirus ribonucleotide reductases and a potentiator of the antiviral activity of acyclovir (ACV) (T. Spector, J. A. Harrington, R. W. Morrison, Jr., C. U. Lambe, D. J. Nelson, D. R. Averett, K. Biron, and P. A. F
4、urman, Proc. Natl. Acad. Sci. USA 86:1051-1055,1989) that was subsequently found to cause hematological toxicity at high oral doses in rats. Eleven structurally related inactivators of herpes simplex virus (HSV) ribonucleotide reductase were therefore tested in vivo for hematological toxicity and fo
5、r potentiation of ACV. None of the novel ribonucleotide reductase inactivators was hematologically toxic to rats following oral dosing at 60 mg/kg/day for 30 days. Four of these inactivators statistically improved the antiviral topical potency of ACV on HSV type 1-infected nude mice. A promising com
6、pound，2-acetylpyridine 5-(2-chloroanilino)thiocarbonylthiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-iofected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus strains
7、tested, i.e.9 wild-type (ACV-sensitive) HSV type 1 and HSV type 2 strains and three mutant (ACV-resistant) HSV type 1 strains. The latter included a virus expressing a DNA polymerase resistant to inhibition by ACV triphosphate, a virus deficient in thymidine kinase (the enzyme responsible for phosph
8、orylating ACV), and a virus expressing an altered thymidine kinase, which catalyzes the normal phosphorylation of thymidine but not of ACV. BW 348U87 and ACV are currently being developed as a combination topical therapy for cutaneous herpes infections.Acyclovir (ACV) is used clinically to treat her
9、pes simplex virus (HSV) and varicella-zoster virus (VZV) infections. It is selectively phosphorylated in herpesvirus-infected cells. The fully activated drug, ACV triphosphate (ACV-TP), competes with dGTP for binding to the target enzyme, herpesvirus DNA polymerase (recently reviewed in references 1
10、1 and 17). Because HSV and VZV code for unusual ribonucleotide reductases that are not subject to the customary allosteric product inhibition of the mammalian counterpart enzymes (5, 6, 20)，they induce the unrestricted synthesis of deoxy- nucleotides (reviewed in references 13 and 14). Consequently,
11、 HSV (and presumably VZV)-infected cells treated with ACV develop increased pools of dGTP, which could impede the binding of ACV-TP to herpesvirus DNA polymerases (3, 16，18). We therefore studied inactivators of herpesvirus ribonucleotide reductases as a means of preventing the buildup of dGTP. Surp
12、risingly, these inactivators not only decreased the dGTP pools but also markedly increased the pools of ACV-TP, thereby enhancing the ACV-TP/dGTP ratio by 90-fold (16, 18). Thus, 2-acetylpyri- dine-4-(2-morpholinoethyl)thiosemicarbazone (A723U), an inactivator of herpesvirus ribonucleotide reductase
13、s，poten- tiates the antiviral activity of ACV in vitro (7，16) and 2- acetylpyridine-5 - (dimethylamino)thiocarbonyithiocarbono- hydrazone (A1110U or BW 1110U81)，a more potent inactivator (10)，potentiates the antiviral activity of ACV in vivo (2, 8) as well as in vitro (18).Unfortunately, in this stu
14、dy, rats dosed orally with BWCorresponding author.1110U81 at 60 mg/kg/day for 30 days developed hematological toxicity. Although a topically applied compound would not be expected to expose humans to comparable levels of BW 1110U81, this toxicity was nevertheless undesirable. We therefore sought saf
15、er inactivators with similar efficacies. In the present study, a series of compounds that had demonstrated apparently selective inactivation of HSV ribonucleotide reductase (1) were tested for hematological toxicity in rats and for antiviral efficacy in combination with ACV on mice. One hematologica
16、lly nontoxic and highly efficacious compound, 2-acetylpyridine5-(2-chloroanilino)thiocarbon- yljthiocarbonohydrazone (BW 348U87), was studied further. The mechanism of inactivation of HSV type 1 (HSV-1) ribonucleotide reductase by BW 348U87 has been reported elsewhere (19).MATERIALS AND METHODSRibonucleotide reductase inactivators. BW 1110U81 was synthesized as previously described (18). Other inactivators were synthesized in our laborato
