Duan J, Liuzzi M, Paris W, Lambert M, Lawetz C, Moss N, Jaramillo J, Gauthier J, Déziel R, Cordingley M G
Bio-Méga Research Division, Boehringer Ingelheim (Canada) Ltd., Laval, Québec, Canada.
Antimicrob Agents Chemother. 1998 Jul;42(7):1629-35. doi: 10.1128/AAC.42.7.1629.
The present study reports the activity of BILD 1633 SE against acyclovir (ACV)-resistant herpes simplex virus (HSV) infections in athymic nude (nu/nu) mice. BILD 1633 SE is a novel peptidomimetic inhibitor of HSV ribonucleotide reductase (RR). In vitro, it is more potent than ACV against several strains of wild-type as well as ACV-resistant HSV mutants. Its in vivo activity was tested against cutaneous viral infections in athymic nude mice infected with the ACV-resistant isolates HSV type 1 (HSV-1) dlsptk and PAAr5, which contain mutations in the viral thymidine kinase gene and the polymerase gene, respectively. Following cutaneous infection of athymic nude mice, both HSV-1 dlsptk and PAAr5 induced significant, reproducible, and persistent cutaneous lesions that lasted for more than 2 weeks. A 10-day treatment regimen with ACV given topically four times a day as a 5% cream or orally at up to 5 mg/ml in drinking water was partially effective against HSV-1 PAAr5 infection with a reduction of the area under the concentration-time curve (AUC) of 34 to 48%. The effects of ACV against HSV-1 dlsptk infection were not significant when it was administered topically and were only marginal when it was given in drinking water. Treatment under identical conditions with 5% topical BILD 1633 SE significantly reduced the cutaneous lesions caused by both HSV-1 dlsptk and PAAr5 infections. The effect of BILD 1633 SE against HSV-1 PAAr5 infections was more prominent and was inoculum and dose dependent, with AUC reductions of 96 and 67% against infections with 10(6) and 10(7) PFU per inoculation site, respectively. BILD 1633 SE also significantly decreased the lesions caused by HSV-1 dlsptk infection (28 to 51% AUC reduction). Combination therapy with topical BILD 1633 SE (5%) and ACV in drinking water (5 mg/ml) produced an antiviral effect against HSV-1 dlsptk and PAAr5 infections that was more than the sum of the effects of both drugs. This is the first report that a selective HSV RR subunit association inhibitor can be effective against ACV-resistant HSV infections in vivo.
本研究报告了BILD 1633 SE对无胸腺裸（nu/nu）小鼠中耐阿昔洛韦（ACV）的单纯疱疹病毒（HSV）感染的活性。BILD 1633 SE是一种新型的HSV核糖核苷酸还原酶（RR）拟肽抑制剂。在体外，它对几种野生型菌株以及耐ACV的HSV突变体比ACV更有效。其体内活性针对感染了耐ACV分离株1型单纯疱疹病毒（HSV-1）dlsptk和PAAr5的无胸腺裸小鼠的皮肤病毒感染进行了测试，这两种病毒分别在病毒胸苷激酶基因和聚合酶基因中含有突变。在无胸腺裸小鼠皮肤感染后，HSV-1 dlsptk和PAAr5均诱导出显著、可重复且持续的皮肤病变，持续超过2周。以5%乳膏每天局部给药4次或在饮用水中以高达5 mg/ml的剂量口服给予ACV进行为期10天的治疗方案，对HSV-1 PAAr5感染有部分疗效，浓度-时间曲线下面积（AUC）降低34%至48%。ACV局部给药时对HSV-1 dlsptk感染的效果不显著，在饮用水中给药时效果也很有限。在相同条件下用5%局部BILD 1633 SE治疗可显著减少由HSV-1 dlsptk和PAAr5感染引起的皮肤病变。BILD 1633 SE对HSV-1 PAAr5感染的效果更显著，且与接种物和剂量相关，每次接种部位感染10(6)和10(7) PFU时，AUC分别降低96%和67%。BILD 1633 SE也显著减少了由HSV-1 dlsptk感染引起的病变（AUC降低28%至51%）。局部BILD 1633 SE（5%）与饮用水中的ACV（5 mg/ml）联合治疗对HSV-1 dlsptk和PAAr5感染产生的抗病毒效果超过了两种药物效果之和。这是关于选择性HSV RR亚基缔合抑制剂可在体内有效对抗耐ACV的HSV感染的首次报道。
