THE EFFICACY OF SAMMA AND ITS LEADING DERIVATIVES AGAINST HIV-1

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 该计划项目的总体目标是开发安全有效的局部抗菌剂，用于阴道或直肠，以阻断人类免疫缺陷病毒(HIV)和包括单纯疱疹病毒(HSV)在内的其他性传播病原体的性传播。整个计划项目的重点是开发一类基于母体化合物二扁桃酸钠乙醚(SAMMA)的新型候选化合物。SAMMA具有良好的抗HIV和HSV活性，同时在组织培养中没有显示出细胞毒性。该方案的项目3侧重于确定SAMMA及其衍生物在生物相关培养系统中的功效。虽然单核细胞培养可能为杀菌剂的评价提供重要信息，但解剖学、生理学和免疫学问题表明，它们可能不能充分模拟发生在人类生殖道液和粘膜组织中的事件。在初步研究中，我们已经证明宫颈阴道灌洗液(CVL)对HSV具有内在的抗病毒活性，对HIV也有较小程度的抗病毒活性。这项辅助研究的目的是进一步鉴定CVL的抗病毒活性。重要的是控制年龄、月经周期和并发感染等因素。因此，我们建议从20名受试者中获得CVL，这些受试者将接受两次评估(相隔2周)。CVL中的抗病毒(HSV和HIV)活性将被检测，并与年龄、月经周期阶段和合并感染的存在相关。此外，还将研究确定抗HSV活性的机制。还将评估SAMMA、主要衍生物和其他候选局部化合物在CVL存在下的稳定性。确定生殖道液中存在的抗病毒活性及其对杀微生物剂活性的影响在开发候选杀微生物剂方面至关重要。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this program project is to develop safe and effective topical antimicrobial agents for vaginal or rectal use that will block sexual transmission of human immunodeficiency virus (HIV) and other sexually transmitted pathogens including herpes simplex virus (HSV). The overall program project focuses on the development of a novel class of candidate compounds based on the parent compound, sodium dimandelic acid ether (SAMMA). SAMMA has excellent anti-HIV and HSV activity, while exhibiting no cytotoxicity in tissue culture. Project 3 of the Program focuses on determining the efficacy of SAMMA and its derivatives in biologically relevant culture systems. While mononuclear cell cultures may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately simulate events that occur in human genital tract fluids and mucosal tissues. In preliminary studies, we have demonstrated that cervicovaginal lavage fluid (CVL) has intrinsic antiviral activity against HSV, and to a lesser extent, HIV. The goal of this ancillary study is to further characterize the anti-viral activity of CVL. It is important to control for factors such as age, menstrual cycle and intercurrent infections. Therefore, we propose to obtain CVL from a cohort of 20 subjects who will be assessed twice (2-weeks apart). The anti-viral (HSV and HIV) activity in the CVL will be assayed and correlated with age, phase of menstrual cycle, and presence of intercurrent infections. In addition, studies to define the mechanism of anti-HSV activity will be conducted. The stability of SAMMA, leading derivatives and other candidate topical compounds in the presence of CVL will also be assessed. Defining the antiviral activity present in genital tract fluids and their impact on microbicide activity is critical in the development of candidate microbicides.