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Novel anti-HIV carrageenan-based on microbicides

基于杀菌剂的新型抗 HIV 角叉菜胶

基本信息

批准号：
6795601
负责人：
David Phillips
金额：
$ 154.34万
依托单位：
POPULATION COUNCIL
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-09-27 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6795601
关键词：
antiviral agents carrageenan chemical structure function communicable disease control drug screening /evaluation

项目摘要

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）：项目主任（也是项目I）的项目负责人[PL]先前开发了卡拉胶杀微生物剂CarraguardTM（PC-515）。卡拉胶属于硫酸化的多糖类化合物，其中许多已知具有抗病毒特性.卡拉胶具有悠久的安全历史，活性成分和目前FDA批准的CalTaguard中的溶剂批准的安全性试验涉及400名妇女与产品使用一年。在该计划旨在提高卡拉胶对艾滋病病毒的有效性， Director开发了两种改良的卡拉胶配方，体外抗HIV和抗单纯疱疹病毒-2（HSV）的活性提高 -2）在小鼠中。一种修饰涉及将锌结合到角叉菜胶上，另一种是加入硫酸化多糖和分散剂，木质素磺酸（LSA）。该项目旨在研究Zn-角叉菜胶和/或LSA-角叉菜胶作为局部杀菌剂。项目主任建议分析这两种制剂在体外阻断不同的HIV毒株和进化枝通过使用PBMC检测，以及他以前开发的检测，其使用来源于人子宫颈的上皮细胞。的制剂还将在小鼠中评估其预防阴道炎的有效性。以及HSV-2的直肠感染，它们阻断HIV运输的能力，以及从阴道穹窿运输单核血细胞的pls 本计划中的其他项目提出以下建议：Howett博士将分析用于阻断人类阴道HIV感染的制剂小鼠系统中的异种移植物。波普博士将评估配方影响树突状细胞介导HIV传播的功能，以及恒河猴预防SIV阴道传播的有效性测定猕猴Anazodo博士将检查稳定性，毒性和 Zn-和LSA-卡拉胶的药代动力学。最后，卡茨博士将检查制剂在体外和体内的铺展和保留性能人类此外，将评价制剂（在所述试验中在储存期间保持活性。在第一次会议结束时，两年后，所有PL调查人员的调查结果将用于优化最终制剂的评价。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剂，其对以下微生物的效力上级：艾滋病。