A practical microbicide based on HIV-1 entry inhibitors

一种基于 HIV-1 进入抑制剂的实用杀菌剂

• 批准号: 7643231
• 负责人: JOHN P MOORE
• 金额: $ 134.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-23 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643231
• 关键词: practical; microbicide; based; HIV; entry

DESCRIPTION (provided by applicant): This IPCP-HTM application made in response to RFA Al-07-001 contains three Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD and co-Principal Investigator, Robin A. Shattock, PhD. The purpose of the program is to conduct in vitro and in vivo pre-clinical and animal model-based research intended to facilitate the development of a vaginal microbicide based on the use of inhibitors of HIV-1 entry, applied alone and/or in combination. Our goal is to use our collective knowledge of virology, immunology, formulation chemistry and mammalian biology to help develop a mechanism-based, HIV-1-specific microbicide(s). An emphasis will be the development and evaluation of long-lasting microbicide formulations and delivery methods, such as controlled release vaginal rings that can provide a continuous and constant supply of active compounds in situ for a period of weeks/months after the application of a single device, and semi-solid formulations that could be applied once-daily or even less frequently. The inhibitors that we will study include, but may not be limited to: the small molecule CCRs inhibitor, CMPDi67 (Merck); the small molecule attachment inhibitor BMS-C (Bristol-Myers Squibb); the small molecule CXCR4 inhibitor AMD3465 (AnorMED); the GP4i-based peptide fusion inhibitor, T-1249 (Trimeris). We propose: Research Project I: Robin Shattock, Characterization of entry inhibitors in human cervical and rectal tissue models, and in dendritic cells; Research Project II: Karl Malcolm, Practical Formulations of HIV-1 Entry Inhibitors; Research Project III: Ronald Veazey, Testing practical microbicides in macaques; Virology and Immunology Core: John P. Moore; Administrative Core: John P. Moore. Other senior members of the team include Melissa Robbiani and Mark Mitchnick (Particle Sciences, Inc) who will participate in Research Projects I and III, respectively, under Cooperative Agreements, and Steven Wolinsky who will take part in the Virology and Immunology Core, also under a Cooperative Agreement. The involvement of Particle Sciences fulfills the mandated corporate element of the proposed research program. If this application is successfully peer reviewed and approved for support by the NIH, the International Partnership for Microbicides will provide the majority of the funding required to support the research programs headed by Drs. Shattock, Robbiani and Wolinsky, as outlined in the Program Overview section of the application. PROJECT 1: Characterization of entry inhibitors in human cervical and rectal tissue models, and dendritic cells (PI Shattock, Robin J.) PROJECT 1 DESCRIPTION (provided by applicant): The potential role of microbicides in preventing the mucosal transmission of HIV-1 has been clearly identified. However, rigorous pre-clinical evaluation of candidate microbicides is essential to the selection of the best compounds for clinical trials, since this will, in the end, provide savings in costs and time, given the expense and length of formal efficacy trials. Concerns with performing efficacy trials with incompletely optimized microbicide candidates have been highlighted by recent failed or halted Phase III trials (COL-1492, SAVVY and Cellulose Sulfate); these trials have suggested that development and formulation of effective microbicides may not be as easy as first thought. While mononuclear cell cultures and animal models may provide important information for the evaluation of microbicides, anatomical, physiological and immunological issues suggest they may not adequately model events that occur in human mucosal tissue. Therefore a comprehensive program for pre-clinical development of microbicide candidates requires that information be accrued from several different model systems. Hence Dr. Shattock's and Robbiani's groups have developed in vitro models of the earliest events in HIV-1 infection of human mucosal tissue and dendritic cell driven HIV-1 spread. These models are ideally suited to test the efficacy of agents designed to block HIV-1 sexual transmission and have been widely used to evaluate potential microbicide candidates. Furthermore, experiments described here and cross validation with experiments described in project III, may identify potential biomarkers of efficacy, safety and compliance that could inform future clinical trials. In this project, we will use these established models to evaluate the efficacy and compatibility of HIV-1 entry inhibitors (alone and in combination) and their formulations. This research will be influenced and guided by work carried out within Core A, and will involve extensive interactions and collaborations with the scientists leading Research Projects II and III. The interactions between the different groups will result in the fast-tracking of the most promising inhibitor combinations and formulations for evaluation in the macaque model (Research Project III).

描述（由申请人提供）：本IPCP-HTM申请应RFA Al-07-001提交，包含三个研究项目，一个科学核心和一个行政核心，由首席研究员John P. Moore博士和联合首席研究员Robin A. Shattock博士指导。该计划的目的是进行体外和体内临床前和动物模型研究，旨在促进基于HIV-1进入抑制剂的阴道杀微生物剂的开发，单独或联合应用。我们的目标是利用我们在病毒学、免疫学、配方化学和哺乳动物生物学方面的集体知识，帮助开发一种基于机制的hiv -1特异性杀微生物剂。重点将是开发和评价持久的杀微生物剂配方和递送方法，例如在使用单一装置后可在原位连续和持续供应活性化合物数周/数月的可控释放阴道环，以及可每天使用一次或甚至更少使用的半固体配方。我们将研究的抑制剂包括但不限于：小分子CCRs抑制剂CMPDi67（默克）；小分子附着抑制剂BMS-C（百时美施贵宝）；小分子CXCR4抑制剂AMD3465 (AnorMED)；基于gp4i的肽融合抑制剂T-1249 （Trimeris）。我们建议：研究项目一：Robin Shattock，人宫颈和直肠组织模型以及树突状细胞中的进入抑制剂的表征；研究项目二：Karl Malcolm， HIV-1进入抑制剂的实用配方；研究项目III: Ronald Veazey，在猕猴身上测试实用杀菌剂；病毒学和免疫学核心：John P. Moore；行政核心：约翰·摩尔。团队的其他高级成员包括Melissa Robbiani和Mark Mitchnick（粒子科学公司），他们将根据合作协议分别参与研究项目I和III，以及Steven Wolinsky，他将根据合作协议参与病毒学和免疫学核心。粒子科学的参与完成了拟议研究计划的强制性公司要素。如果该申请成功通过同行评审并获得NIH的支持，国际杀菌剂伙伴关系将提供所需的大部分资金，以支持由dr。Shattock， Robbiani和Wolinsky，如应用程序的程序概述部分所述。