Practical formulations of HIV-1 entry inhibitors

本IPCP-HTM申请是针对RFA Al-oy-ooi提出的，包含三个研究项目， 科学核心和行政核心，在首席研究员John P.摩尔的指导下， 博士和共同首席研究员，罗宾A。Shattock博士该计划的目的是在 体外和体内临床前和基于动物模型的研究，旨在促进 基于使用HIV-1进入抑制剂的阴道杀微生物剂，其单独和/或组合应用。 我们的目标是利用我们在病毒学、免疫学、制剂化学和 哺乳动物生物学，以帮助开发一种基于机制的HIV-i特异性杀微生物剂。强调将 开发和评价长效杀微生物剂配方和投放方法，例如 控释阴道环可提供活性化合物的连续和恒定供应， 在施用单个装置后原位施用数周/数月的时间，以及半固体制剂， 可以每天施用一次或更少的频率。我们将研究的抑制剂包括，但可能不包括 限于：小分子CCR抑制剂，CMPDi 67（Merck）;小分子连接 抑制剂BMS-C（Bristol-Myers Squibb）;小分子CXCR 4抑制剂AMD 3465（AnorMED）; 基于gp 4 i的肽融合抑制剂，T-1249（Trimeris）。我们建议：研究项目I：罗宾·沙托克， 人宫颈和直肠组织模型以及树突状细胞中进入抑制剂的表征; 研究项目II：Karl Malcolm，HIV-i进入抑制剂的实用配方;研究项目III： 罗纳德维齐，在猕猴中测试实用的杀微生物剂;病毒学和免疫学核心：约翰P。 摩尔;行政核心：约翰·P.摩尔。该团队的其他高级成员包括梅丽莎·罗比亚尼 和Mark Mitchnick（粒子科学公司），他们将参与研究项目I和III， 根据合作协议，史蒂文·沃林斯基将参加病毒学和 免疫学核心，也根据合作协议。粒子科学的参与实现了 建议的研究计划的强制性企业元素。如果这份申请通过同行评审 并得到NIH的批准，国际杀微生物剂伙伴关系将 提供大部分所需的资金来支持由Shattock博士领导的研究项目， Robbiani和Wolinsky，如应用程序的程序概述部分所述。

This IPCP-HTM application made in response to RFA Al-oy-ooi 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-i 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-i-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-i 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 peerreviewed 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.