Phase II SBIR: 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。II期工作的目标是进一步开发WHI-07，一种新型的5-溴- 6-甲氧基芳基磷酰胺衍生物，作为3'-叠氮-3'-脱氧胸苷（zidovudine, ZDV/AZT）的双功能抗hlv杀菌剂。WHI-07设计合理，可绕过生殖道分泌物中ZDV激活的胸苷激酶依赖性。WHI-07是通过一种无毒凝胶微乳液制成的，作为一种潜在的抗hiv杀精剂。WHI-07的体内疗效和安全性研究包括：(i)阴道和直肠杀微生物剂对猫免疫缺陷病毒(FIV)/家猫艾滋病模型的疗效研究；（ii）在非人类灵长类动物体内保留抗hiv活性；（iii）家兔阴道避孕效果研究；（iv）小鼠、兔子、猫和猴子的单剂量和/或多剂量毒性研究；(v)小鼠和家兔的粘膜、生殖和发育毒性研究；㈥使用人类和酵母细胞进行细胞毒性、诱变性和基因毒性试验；（七）小鼠长期致癌性研究。根据第一阶段的建议，我们测试了(I) WHI-07在家猫中预防经阴道和经直肠传播FIV的能力，作为HIV性传播的模型；（ii）确定WHI-07在家兔模型中无发育毒性。我们发现，WHI-07单独或与双（环戊二烯基）钒（IV）络合物钒二硫代氨基甲酸盐（VDDTC）联合使用，通过生殖器暴露于粘膜传播的FIV感染的猫T细胞，有效地保护家猫免受全身FIV感染，这一发现具有开发用于性活跃女性的双功能抗hiv杀菌剂的临床潜力。在II期资助下，我们拟开展WHI-07联合VDDTC凝胶微乳的体内抗逆转录病毒和避孕效果以及安全性研究，进一步探索WHI-07单独使用或与VDDTC联合使用作为阴道杀精抗hiv杀菌剂的临床应用。我们假设，与单独使用WHI-07相比，这两种具有不同作用机制的活性药物联合使用可能会提高双重保护的疗效和持续时间，同时保持足够的安全性。II期研究的目标是：(i)检验WHI-07加VDDTC凝胶微乳液与单独WHI-07相比，在预防经阴道和经直肠感染FIV细胞的家猫系统性FIV感染方面的最佳杀微生物活性；（ii）评价WHI-07加VDDTC凝胶微乳在家兔体内的避孕效果；（iii）评价WHI-07加VDDTC凝胶微乳对家兔的粘膜安全性和发育毒性；（iv）评价WHI-07加VDDTC凝胶微乳的稳定性。拟议的II期工作将补充和加强Paradigm Pharmaceuticals安全有效的双功能杀微生物剂的发现和临床前开发，这可能为预防艾滋病毒性传播的新策略提供基础，同时为妇女提供有效的生育控制。

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. The goal of the proposed Phase II work is to further develop WHI-07, a novel 5-bromo 6-methoxy aryl phosphoramidate derivative of 3'-azido-3'-deoxythymidine (zidovudine, ZDV/AZT) as a dual-function anti-HlV microbicide. WHI-07 was rationally designed to bypass the thymidine kinase dependency of ZDV activation in genital tract secretions. WHI-07 was formulated via a nontoxic gel-microemulsion for intravaginal use as a potential candidate anti-HIV spermicide. The in vivo efficacy as well as safety studies of WHI-07 have included: (i) vaginal as well as rectal microbicide efficacy studies in the feline immunodeficiency vires (FIV)/domestic cat model for AIDS; (ii) in vivo retention of anti-HIV activity in the nonhuman primate; (iii) vaginal contraceptive efficacy studies in rabbits; (iv) single- and/or multiple-dose toxicity studies in mice, rabbits, cats as well as monkey; (v) mucosal, reproductive, and developmental toxicity studies in mice and rabbits; (vi) cytotoxicity, mutagenicity, and genotoxicy tests using human and yeast cells; and (vii) long-term carcinogenicity studies in mice. Under Phase I proposal we tested: (i) the ability of WHI-07 to prevent transvaginal as well as transrectal transmission of FIV in domestic cats as a model for sexual transmission of HIV; and (ii) determined the lack of developmental toxicity of WHI-07 in the rabbit model. Our discovery that WHI-07 either alone or in combination with a bis(cyclopentadienyl) vanadium(IV) complex, vanadocene dithiocarbamate (VDDTC), effectively protected domestic cats from systemic FIV infection via genital exposure to mucosally transmissible FIV-infected feline T cells has clinical potential for the development of a dual-function anti-HIV microbicide for sexually active women. Under Phase II funding, we propose to test the in vivo antiretroviral and contraceptive efficacies as well as safety studies of WHI-07 plus VDDTC gel-microemulsion to further explore the utility of WHI-07 either alone and in combination with VDDTC as a vaginal spermicidal anti-HIV microbicide in the clinical setting. We hypothesize that the combination of these two active agents with different mechanisms of action will potentially improve efficacy and duration of dual-protection when compared to WHI-07 alone while maintaining an adequate safety profile. The goals of Phase II study are (i) to examine the optimum microbicide activity of WHI-07 plus VDDTC gel-microemulsion versus WHI-07 alone to prevent systemic FIV infection of domestic cats from transvaginal and transrectal challenge with FIV-infected cells; (ii) to evaluate the in vivo contraceptive efficacy of WHI-07 plus VDDTC gel-microemulsion in rabbits; (iii) to assess the mucosal safety and developmental toxicity of WHI-07 plus VDDTC gel-microemulsion in rabbits; and (iv) to assess the stability WHI-07 plus VDDTC in-gel-microemulsion. The proposed Phase II work will complement and enhance the discovery and preclinical development of safe and effective dual-function microbicides at Paradigm Pharmaceuticals that may provide the basis for a new strategy to prevent the sexual transmission of HIV while providing effective fertility control for women.