Spector T, Lobe D C, Ellis M N, Blumenkopf T A, Szczech G M
Division of Experimental Therapy, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709.
Antimicrob Agents Chemother. 1992 May;36(5):934-7. doi: 10.1128/AAC.36.5.934.
A1110U (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. Furman, 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 for 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 compound, 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl]thiocarbonohydrazone (BW 348U87), was studied more extensively in two in vivo models: dorsum-infected athymic nude mice and snout-infected hairless mice. BW 348U87 significantly potentiated the antiviral activity of ACV against all virus strains tested, i.e., 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 phosphorylating 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.
A1110U（BW 1110U81）是一种疱疹病毒核糖核苷酸还原酶的灭活剂，也是阿昔洛韦（ACV）抗病毒活性的增效剂（T. 斯佩克特、J. A. 哈林顿、小R. W. 莫里森、C. U. 兰贝、D. J. 纳尔逊、D. R. 埃弗里特、K. 比龙和P. A. 弗曼，《美国国家科学院院刊》86:1051 - 1055，1989年），后来发现其在大鼠口服高剂量时会引起血液学毒性。因此，对11种结构相关的单纯疱疹病毒（HSV）核糖核苷酸还原酶灭活剂进行了体内血液学毒性和ACV增效作用的测试。在以60毫克/千克/天的剂量口服给药30天后，这些新型核糖核苷酸还原酶灭活剂对大鼠均无血液学毒性。其中4种灭活剂在统计学上提高了ACV对1型HSV感染的裸鼠的局部抗病毒效力。一种有前景的化合物，2 - 乙酰吡啶5 - [（2 - 氯苯胺基）硫代羰基]硫代碳酰肼（BW 348U87），在两种体内模型中进行了更广泛的研究：背部感染的无胸腺裸鼠和口鼻部感染的无毛小鼠。BW 348U87显著增强了ACV对所有测试病毒株的抗病毒活性，即野生型（对ACV敏感）1型HSV和2型HSV毒株以及三种突变型（对ACV耐药）1型HSV毒株。后者包括一种表达对ACV三磷酸抑制有抗性的DNA聚合酶的病毒、一种缺乏胸苷激酶（负责将ACV磷酸化的酶）的病毒以及一种表达改变的胸苷激酶的病毒，该酶催化胸苷的正常磷酸化但不催化ACV的磷酸化。BW 348U87和ACV目前正在开发用于皮肤疱疹感染的联合局部治疗。
