WHI-07: A Novel Dual-Function Microbicide

描述（由申请人提供）：目前性传播的艾滋病毒/艾滋病大流行迫切需要一种新型杀微生物剂：一种既是杀精剂又是杀病毒剂的杀微生物剂。为了系统地鉴定一种非洗涤剂型抗病毒杀精剂，我们用氯化磷化学方法合成了一系列新的溴甲氧基西多夫定[ZDV]的芳基磷酸衍生物，并检测了其抗hiv和杀精的双重功能。与ZDV不同，我们的先导化合物WHI-07，[5-溴-6-甲氧基-5,6-二氢-3 '-氮基胸腺嘧啶-5 '-(对溴苯氧基z}-甲氧基丙氨酸磷酸]，表现出有效的抗wiv和杀精活性。WHI-07被合理设计为绕过生殖道白细胞中ZDV激活的胸苷激酶依赖性。其抗hiv活性所需的WHI-07浓度比壬氧醇- 9en -91低439倍。WHI-07的杀精活性是N-9的14倍，对女性生殖道上皮细胞的细胞毒性无关。在临床前研究中，全身或阴道给予WHI-07，在小鼠、兔子和食蟹猴中没有炎症和毒性作用，在体外和体内的致突变性和致癌性试验中没有基因毒性。我们推测，WHI-07由于其强大的抗HIV活性、杀精效果以及无炎症和毒性作用，可能对通过性传播感染HIV/AIDS的高风险妇女作为一种双功能阴道阴道杀微生物剂有用。第一阶段计划的目标是测试：(I) WHI-07凝胶制剂在家猫中预防猫免疫缺陷病毒阴道传播的能力，作为艾滋病毒性传播的模型；(2)确定WHI-07凝胶制剂在兔模型中的发育毒性，这些目标的成功实现可能为预防HIV性传播的新策略提供基础，同时为妇女提供生育控制。在成功完成I期体内疗效和安全性研究后，WHI-07凝胶制剂将在II期进一步探索作为阴道双功能杀微生物剂。

DESCRIPTION (provided by applicant): The current pandemic of sexually transmitted HIV/AIDS has created an urgent need for a new type of microbicide: one that is both a spermicide and a virucide. In a systematic effort to identify a non-detergent-type antiviral spermicide, we have synthesized a series of novel aryl phosphate derivatives of bromo-methoxy cidovudine [ZDV ] by phosphorochloridate chemistry and examined for dual-function anti-HIV and spermicidal xtivities. Unlike ZDV, our lead compound WHI-07, [5-bromo-6-methoxy-5,6-dihydro-3 '-azidothymidine- 5'-(p-bromophenyZ}- methoxy alaninyl phosphate], exhibited potent anti-WIV as well as spermicidal activities. WHI-07 was rationalIy designed to bypass the thymidine kinase-dependency of ZDV activation in genital tract leukocytes. The concentration of WHI-07, required for its anti-HIV activity was 439-fold lower than that of nonoxynol-9 EN-91. The spermicidal activity of WHI-07 was 14-fold more potent than that of N-9 and it was not associated with cytotoxicity to female genital tract epithelial cells. Preclinical studies of WHI-07 given systemically or intravaginally , lacked inflammatory and toxic effects in mice, rabbits, and cynomolgus monkeys and was nongenotoxic in in vitro and in vivo mutagenicity and carcinogenicity tests. We hypothesize that WHI-07, because of its potent anti-HIV activity, spermicidal efficacy, and lack of inflammatory and toxic effects, may be useful as a dual-function vaginalkectal microbicide for women who are at high risk of acquiring HIV/AIDS by sexual transmission. The goal of this Phase I proposal is to test: (i) the ability of WHI-07 gel formulation to prevent vaginal transmission of feline immunodeficiency virus in domestic cats as a model for sexual transmission of HIV; and (ii) to determine the developmental toxicity of WHI-07 gel formulation in the rabbit model, The successful accomplishment of these goals may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing fertility control for women. Following successful completion of the Phase I in vivo efficacy and safety studies, gel formulations of WHI-07 will be further explored as a vaginal dual-function microbicide in Phase II.