AFE inhibitor combinations as HIV1 topical microbicides

AFE 抑制剂组合作为 HIV1 局部杀菌剂

• 批准号: 6952642
• 负责人: JOHN P MOORE
• 金额: $ 186.49万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6952642
• 关键词: AIDS education /prevention; antiAIDS agent; chemoprevention; clinical research; cooperative study; drug screening /evaluation; local antiinfective agents; topical drug application

DESCRIPTION (provided by applicant): This IPCP-HTM application constitutes three Research Projects, one Research Support Core and an Administration Core, under the direction of Principal Investigator, John P. Moore, PhD and co-Principal Investigator, Robin Shattock, PhD. The purpose of the program is to conduct in vitro and in vivo pre-clinical and animal model-based research intended to identify and characterize combinations of inhibitors of HIV-1 entry that might be suitable for development as topical microbicides, then test the most suitable candidates for safety in uninfected women. Our central hypothesis is that combinations of specific inhibitors of HIV-1 attachment, fusion and entry (AFE inhibitors) could prevent HIV-1 sexual transmission, when properly formulated and applied by women or men prior to intercourse. We believe microbicide design should be based on rational scientific principles, taking into account accumulated knowledge of the stages of the viral life cycle to be impeded, the mechanism of action of candidate inhibitors, and the biological processes involved in HIV-1 transmission. We do not intend to study microbicide candidates that act non-specifically, that have a broad-spectrum activity against multiple pathogens, or that are also spermicides. Our goal is to use our knowledge of virology and mammalian biology to help develop a mechanism-based, HIV-1-specific microbicide(s). Hence, we will evaluate combinations of different inhibitors of defined stages in HIV-1 entry. We will move the best inhibitors into a safety trial in the later years of the project. We propose: Research Project I: Robin Shattock. Characterization of HIV-1 AFE inhibitors in human cervical and rectal tissue models; Research Project II: Melissa Pope. Assessment of AFE inhibitors in DC-T cell mixtures; Research Project III: Ronald Veazey. Evaluation of AFE inhibitors for protection from SHIV vaginal challenge in macaques; Research Project IV: Charles Lacey. Safety studies of AFE inhibitors in normal women; Core A: John P. Moore. Inhibitor Acquisition, Evaluation and Formulation; Core B: John P. Moore. Administration.

描述（由申请人提供）：该 IPCP-HTM 申请由三个研究项目组成，一个研究支持核心和一个管理核心，由首席研究员 John P. Moore 博士和联合首席研究员 Robin Shattock 博士指导。该计划的目的是进行体外和体内临床前和基于动物模型的研究，旨在识别和表征可能适合开发为局部杀菌剂的 HIV-1 进入抑制剂组合，然后测试最合适的组合未感染女性的安全候选者。我们的中心假设是，如果女性或男性在性交前正确配制和使用，HIV-1 附着、融合和进入的特异性抑制剂（AFE 抑制剂）的组合可以预防 HIV-1 性传播。我们认为，杀微生物剂的设计应基于合理的科学原理，同时考虑到所积累的要阻碍的病毒生命周期各阶段的知识、候选抑制剂的作用机制以及涉及 HIV-1 传播的生物过程。我们无意研究非特异性作用、对多种病原体具有广谱活性或同时也是杀精剂的候选杀微生物剂。我们的目标是利用我们的病毒学和哺乳动物生物学知识来帮助开发一种基于机制的 HIV-1 特异性杀菌剂。因此，我们将评估 HIV-1 进入特定阶段的不同抑制剂的组合。我们将在项目的后期将最好的抑制剂转移到安全试验中。我们建议：研究项目一：Robin Shattock。 HIV-1 AFE 抑制剂在人类宫颈和直肠组织模型中的表征；研究项目二：梅丽莎·波普。 DC-T细胞混合物中AFE抑制剂的评估；研究项目三：罗纳德·维泽。评估 AFE 抑制剂对猕猴免受 SHIV 阴道攻击的保护作用；研究项目四：查尔斯·莱西。 AFE抑制剂在正常女性中的安全性研究；核心A：约翰·P·摩尔。抑制剂的获取、评估和配制；核心 B：约翰·P·摩尔。行政。