CYCLODEXTRIN AS NOVEL SPERMICIDE AND MICROBICIDE

描述（由申请人提供）：当地应用的生物医学屏障和 杀微生物剂已被证明在预防艾滋病毒的性传播方面无效。 我们最近发现，艾滋病毒需要完整的脂筏，高度专业化， 细胞膜中的亚区，用于进入细胞和完全出芽 传染性粒子β-环糊精（β-CD），一种环状七糖 从细胞膜中去除胆固醇并分散脂筏， 已被证明可以阻止艾滋病毒感染，并大大降低 艾滋病病毒的萌芽胆固醇也是其他病原体所必需的， 与性传播疾病有关。β-环糊精是无毒的， 人类用作极性药物载体。经过适当的调配，这种分子 可能是一种有效的杀微生物剂，具有抗HIV和其他病原体的活性。 胆固醇已被证明在调节精子细胞顶体 β-CD诱导的精子细胞胆固醇反应和消耗 获能和过早的顶体反应。后者与 受精率低。因此β-CD通过消耗精子细胞 胆固醇，可能通过诱导过早的顶体， 反应和降低聚变效率。这个问题的核心假设是 建议是，因为它快速有效地消耗胆固醇， 脂膜β-CD具有很大的潜力， 具有低宿主细胞毒性的杀微生物剂-杀精子剂。这个项目的目标是 使用体外和体内动物模型来测试β-CD作为 杀微生物剂，特别是抗艾滋病毒和杀精剂，并确定 β-CD灭活H1 V的机制。具体目标是：1.到 β-环糊精对HIV-1的抑制作用的表征和优化 感染2.为了确定β-环糊精 灭活无细胞HIV-1颗粒。3.为了确定 β-环糊精灭活细胞相关的HIV-1。4.确定 β-环糊精对家兔避孕模型中精子功能的影响。 5.确定β-环糊精对细菌病原体的体外作用 和阴道植物群。6.为了确定抗HIV杀微生物剂的潜力， Hu-PBL-SCID小鼠阴道攻击模型中的β-环糊精。7.到 确定β-环糊精对HSV的杀微生物潜力， 乳头瘤病毒和沙眼衣原体。本项目以 胆固醇在精子生物学中的共同重要性的优势， 艾滋病毒和其他病原体，以开发一种新的杀微生物剂/避孕方法。

DESCRIPTION (provided by applicant): Locally applied biomedical barriers and microbicides have proven ineffectual in preventing sexual transmission of HIV. We have recently found that HIV requires intact lipid rafts, highly specialized subregions in cell membranes, for entry into cells and for budding of fully infectious particles. Beta-cyclodextrin (beta-CD), a cyclic heptasaccharide that removes cholesterol from cell membranes and disperses lipid rafts, has been shown to block HIV infection and drastically reduce the infectivity of budding HIV particles. Cholesterol is also required by other pathogens some of which are associated with STDs. Beta-cyclodextrin is non-toxic and currently in human use as a carrier for polar drugs. Thus properly formulated, this molecule may be an effective microbicide with activity against HIV and other pathogens. Cholesterol has been shown to play a role in regulating sperm cell acrosomal reaction and depletion of sperm cell cholesterol by beta-CD induces capacitation and premature acrosomal reaction. The latter has been associated with low rates of fertilization. Thus beta-CD, by depleting sperm cell cholesterol, may prevent fertilization in vivo by inducing premature acrosomal reactions and reducing fusion efficiency. The central hypothesis of this proposal is that because it rapidly and efficiently depletes cholesterol from lipid membranes beta-CD has great potential as a combination microbicide-spermicide with low host cell toxicity. The goal of this project is to use in vitro and in vivo animal models to test the potential of beta-CD as a microbicide, particularly against HIV, and spermicide and to determine the mechanisms by which beta-CD inactivates H1V. The specific aims are: 1. To characterize and optimize the inhibitory effect of Beta-cyclodextrin on HIV-1 infection. 2. To determine the mechanisms by which Beta-cyclodextrin inactivates cell-free HIV-1 particles. 3. To determine the mechanisms by which Beta-cyclodextrin inactivates cell-associated HIV-1. 4. To determine the effects of Beta-cyclodextrin on sperm function in a rabbit contraception model. 5. To determine the effect of Beta-cyclodextrin in vitro on bacterial pathogens and vaginal flora. 6. To determine the anti-HIV microbicide potential of Beta-cyclodextrin in a Hu-PBL-SCID mouse vaginal challenge model. 7. To determine the microbicide potential of Beta-cyclodextrin against HSV, papillomavirus, and chlamydia trachomatis in animal models. This project takes advantage of the shared importance of cholesterol in the biology of sperm and HIV and other pathogens to develop a novel microbicide/contraceptive approach.