Novel anti-HIV carrageenan-based on microbicides

基于杀菌剂的新型抗 HIV 角叉菜胶

• 批准号: 6651962
• 负责人: David Phillips
• 金额: $ 151.57万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6651962
• 关键词: antiviral agents; carrageenan; chemical structure function; communicable disease control; drug screening /evaluation

DESCRIPTION (provided by applicant): The Program Director (who is also the Project Leader [PL] of Project I) has previously developed the carrageenan microbicide, CarraguardTM (PC-515). Carrageenan belongs to the sulfated polysaccharide class of compounds, many of which are known to have anti-viral properties. Carrageenan, which has a long history of safety, is both the active ingredient and the vehicle in CalTaguard that is currently in FDA approved safety trials involving 400 women with product use for one year. In an effort to increase the efficacy of carrageenan against HIV, the Program Director has developed two modified carrageenan formulations that have shown improved activity against HIV in vitro and against herpes simplex virus-2 (HSV -2) in mice. One modification involves binding zinc to carrageenan and the other is the addition of the sulfated polysaccharide and dispersing agent, lignosulfonic acid (LSA). This Program Project is directed toward investigating the potential of Zn-carrageenan and/or LSA-carrageenan as topical microbicide(s). The Program Director proposes to assay the activity of the two formulations in blocking different strains and clades of HIV in vitro by utilizing a PBMC assay, as well as an assay that he previously developed which employs epithelial cells derived from the human cervix. The formulations will also be evaluated in mice for their effectiveness in preventing vaginal and rectal infection by HSV -2, their ability to block the transport of HIV, and the trafficking of mononuclear blood cells from the vaginal vault. The PLs of other projects in this Program propose the following: Dr. Howett will assay the formulations for efficacy in blocking HIV infection of human vaginal xenografts in a mouse system. Dr. Pope will evaluate how formulations influence dendritic cell function in mediating transmission of HIV, as well as assaying for efficacy in preventing vaginal transmission of SIV in rhesus macaques. Dr. Anazodo will examine the stability, toxicity and pharmacokinetics of Zn-, and LSA-carrageenan. Lastly, Dr. Katz will examine the spreading and retention properties of the formulations in vitro and in humans. Additionally, formulations will be evaluated (in the assays mentioned above) for retaining activity during storage. At the conclusion of the first two years, the findings of all PLs Investigators will be used for the optimization of an evaluation for a final formulation(s). The applicant believes that the proposed research will result in the pre-clinical development of a safe, novel microbicide that is superior in efficacy against HIV.

描述（由申请人提供）：计划主任（他也是 项目负责人[PL]项目i）以前已经开发了Carrageenan 菌心，carraguardtm（PC-515）。角叉菜胶属于硫酸盐 多糖类化合物类别，其中许多含有抗病毒 特性。角叉菜胶具有悠久的安全历史，是 目前在FDA中的有源成分和Caltaguard的车辆 批准的安全试验涉及400名产品使用一年的妇女。在 该计划的努力提高角叉菜胶对艾滋病毒的疗效，该计划 导演已经开发了两种改良的角叉菜胶配方 在体外和针对单纯疱疹病毒-2中对HIV的活性改善（HSV -2）在小鼠中。一种修饰涉及与角叉菜胶结合的结合和 其他是添加硫酸化的多糖和分散剂， 木质硫酸（LSA）。该计划项目针对 研究Zn-Carrageenan和/或LSA-Carrageenan的潜力 局部菌心（S）。该计划主管建议测定 在体外阻断不同菌株和HIV的进化枝的两个配方 通过使用PBMC测定法以及他以前开发的测定法 它采用源自人宫颈的上皮细胞。配方 还将在小鼠中评估它们在预防阴道的有效性 HSV -2的直肠感染，它们阻止HIV的运输能力， 以及从阴道穹顶中贩运单核血细胞。 PLS 该计划中的其他项目提出以下建议：Howett博士将分析 阻断人类阴道艾滋病毒感染有效性的制剂 鼠标系统中的异种移植物。教皇博士将评估配方的方式 影响树突状细胞功能在介导HIV的传播以及 测定预防恒河类阴道传播的功效 猕猴。 Anazodo博士将检查稳定性，毒性和 Zn-和LSA-Carrageenan的药代动力学。最后，卡兹博士将检查 在体外和IN中配方的扩展和保留特性 人类。此外，将评估配方（在提到的测定中 上面）用于保留存储期间的活动。在第一个结束时 两年来，所有PLS调查人员的发现都将用于 最终公式评估的优化。申请人 认为拟议的研究将导致临床前 开发一种安全的新型杀微生物，在功效方面具有优越性 艾滋病病毒。