Partnership for developing broad-spectrum microbicides

描述(由申请者提供)：该研究项目建议药物研究公司梅迪尔AB(瑞典)与非营利性非政府组织人口理事会(美国)建立合作伙伴关系。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组合杀菌剂，以阻断HIV-1和HIV-2、乙肝病毒(乙肝病毒)和单纯疱疹病毒-2(HSV-2)的感染。MEDIVR AB将从他们详尽的潜在抗病毒药物库中分析约2000个NNRTI(S)，以了解其与艾滋病毒和乙肝病毒逆转录酶结合的能力。血浆共振法将被用来确定重组病毒聚合酶的开启和关闭结合率。具有最佳开/关结合率的化合物将由PI分析。人口委员会的CarraGuard在体外和动物实验中证明了对艾滋病毒和其他性传播病原体的有效性。理事会将优化以CarraGuard为基础的抗病毒制剂(S)(CBAVs)，其中包含NNRT1(S)和抗HSV化合物(S)，以用于一种对广谱性传播感染有效的“鸡尾酒”杀菌剂。CBAVs将在以下方案中进行筛选：评估稳定性的3阶段方案；评估毒性的3阶段方案；以及评估体外和体内药代动力学特征的2阶段方案。将评估针对HIV-1临床分离株的有效性，重点是C亚型病毒和HIV-2。此外，在体外和HSV-2/小鼠系统中，CBAVs将与CarraGuard进行抗乙肝病毒和抗HSV-2的疗效比较。我们的目标是通过添加对艾滋病毒-1、艾滋病毒-2、乙肝病毒和单纯疱疹病毒-2具有活性的抗病毒化合物来提高该制剂对更广泛的性传播疾病(STD)的疗效，并增加其强度。

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.