Phase II SBIR: WHI-07: A Novel Dual-Function Microbicide

描述（由申请人提供）：目前性传播艾滋病毒/艾滋病的流行迫切需要一种新型的杀微生物剂：一种既是杀精剂又是杀病毒剂。所提出的II期工作的目标是进一步开发WHI-07，一种新的3 ′-叠氮基-3 ′-脱氧胸苷（齐多夫定，ZDV/AZT）的5-溴6-甲氧基芳基氨基磷酸酯衍生物，作为双功能抗HIV杀微生物剂。合理设计WHI-07以绕过生殖道分泌物中ZDV活化的胸苷激酶依赖性。WHI-07通过无毒凝胶微乳液配制用于阴道内使用，作为潜在的候选抗HIV杀精剂。WHI-07的体内功效以及安全性研究包括：（i）在猫免疫缺陷病毒（FIV）/家猫AIDS模型中的阴道以及直肠杀微生物剂功效研究;（ii）在非人灵长类动物中抗HIV活性的体内保留;（iii）在兔中的阴道避孕功效研究;（iv）对小鼠、家兔、猫和猴进行的单次和/或多次给药毒性研究;（v）对小鼠和家兔进行的粘膜、生殖和发育毒性研究;（vi）使用人类和酵母细胞进行的细胞毒性、致突变性和遗传毒性试验;和（vii）小鼠长期致癌性研究。在I期提案中，我们测试了：（i）WHI-07在作为HIV性传播模型的家猫中预防FIV经阴道和经直肠传播的能力;和（ii）确定WHI-07在兔模型中缺乏发育毒性。我们发现WHI-07单独或与双（双）钒（IV）络合物二硫代氨基甲酸二茂钒（VDDTC）组合，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系统性FIV感染，这对于开发用于性活跃女性的双功能抗HIV杀微生物剂具有临床潜力。在第二阶段的资助下，我们建议测试体内抗逆转录病毒和避孕的功效，以及安全性研究的WHI-07加VDDTC凝胶-微乳液，以进一步探索WHI-07单独或与VDDTC组合作为阴道杀精抗HIV微生物剂在临床环境中的效用。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的组合可能会改善双重保护的疗效和持续时间，同时保持足够的安全性。II期研究的目的是（i）检查WHI-07加VDDTC凝胶-微乳剂与单独WHI-07相比的最佳杀微生物活性，以预防家猫通过经阴道和经直肠用FIV感染的细胞攻击的全身性FIV感染;（ii）评价WHI-07加VDDTC凝胶-微乳剂在兔中的体内避孕功效;（iii）评估WHI-07加VDDTC凝胶-微乳在兔中的粘膜安全性和发育毒性;以及（iv）评估WHI-07加VDDTC凝胶-微乳中的稳定性。拟议的第二阶段工作将补充和加强Paradigm制药公司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战略提供基础，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.