Partnership for developing broad-spectrum microbicides

描述（由申请人提供）：本研究项目提出药物研究公司Medivir AB（瑞典）和非营利性非政府组织人口委员会（美国）之间的合作伙伴关系。目的是开发一种含有两种或两种以上活性药物成分的新型联合杀微生物剂，以阻断HIV-1和2、乙型肝炎病毒（HBV）和单纯疱疹病毒-2 （HSV-2）的感染。Medivir AB将从他们的潜在抗病毒药物库中检测大约2000种NNRTI(s)与HIV和HBV逆转录酶结合的能力。等离子体共振试验将用于确定在和关闭结合率使用重组病毒聚合酶。具有最佳开/关结合率的化合物将通过pi进行分析。在体外和动物实验中，人口理事会的Carraguard已证明对艾滋病毒和其他性传播病原体有效。理事会将优化含有NNRTl和抗hsv化合物的基于Carraguard的抗病毒制剂（cavs），用于对广谱性传播感染有效的“鸡尾酒”杀微生物剂。cbav将在以下方案中进行筛选：评估稳定性的3阶段方案；一个评估毒性的3阶段方案；还有一个评估体内和体外药代动力学的两阶段方案。对临床分离的HIV-1（重点是C亚型病毒）和HIV-2的有效性将进行评估。此外，cavs将与Carraguard在体外抗HBV和在HSV-2/小鼠系统中对HSV-2的有效性进行比较。我们的目标是通过添加对HIV-1、HIV-2、HBV和HSV-2有效的抗病毒化合物来提高配方对更广泛的性传播疾病（std）的功效，并提高其强度。

DESCRIPTION (provided by applicant): This research project proposes a partnership between the drug research company Medivir AB (Sweden) and the nonprofit, nongovernmental organization, Population Council (US). The aim is to develop a novel combination microbicide containing two or more active pharmaceutical ingredients to block infection by HIV-1 and 2, hepatitis B virus (HBV) and herpes simplex virus-2 (HSV-2). Medivir AB will assay about 2000 NNRTI(s) from their exhaustive library of potential anti-virals for ability to bind to HIV and HBV retrotranscriptases. The plasmon resonance assay will be used to determine on and off binding rates using recombinant viral polymerases. Compounds with the best on/off binding rates will be analyzed by the PIs. The Population Council's Carraguard has demonstrated efficacy against HIV and other sexually transmitted pathogens in vitro and in animal studies. The Council will optimize Carraguard Based Antiviral formulation(s) (CBAVs) containing NNRTl(s) and anti-HSV compound(s) for use in a "cocktail" microbicide efficacious against a broadspectrum of STIs. CBAVs will be screened in the following regimens: a 3-stage regimen assessing stability; a 3-stage regimen assessing toxicity; and a 2-stage regimen assessing in vitro and in vivo pharmacokinetic profiles. Effectiveness against clinical isolates of HIV-1, with emphasis on subtype C viruses, and HIV-2 will be evaluated. Additionally, CBAVs will be compared to Carraguard in vitro against HBV and in the HSV-2/mouse system for efficacy against HSV-2. Our goals are to improve the formulation's efficacy against a broader range of sexually transmitted diseases (STDs) and increase its strength by adding anti-viral compounds that are active against HIV-1, HIV-2, HBV and HSV-2.