Practical formulations of HIV-1 entry inhibitors

这份IPCP-HTM申请是对RFA Al-Oy-OOI的回应，它包含三个研究项目，一个 科学核心和行政核心，在首席调查员约翰·P·摩尔的指导下， 博士和联合首席调查员，Robin A.Shattock博士。该计划的目的是在 体外和体内临床前和动物模型研究旨在促进 基于使用HIV-I进入抑制剂的阴道杀菌剂，单独和/或组合使用。 我们的目标是利用我们在病毒学、免疫学、配方化学和 哺乳动物生物学帮助开发一种以机制为基础的、针对艾滋病毒I的杀微生物剂(S)。重点将是 开发和评价长效杀微生物剂配方和给药方法，例如 控释阴道环，可提供持续和恒定的活性化合物供应 在应用单一装置后原位进行数周/数月的时间，以及半固体制剂 可以每天使用一次，甚至更少使用。我们将研究的抑制剂包括，但可能不包括 仅限于：小分子CCRS抑制剂CMPDi67(默克)；小分子结合 抑制剂BMS-C(百时美施贵宝)；小分子CXCR4抑制剂AMD3465(AnorMED)； 基于gp4i的多肽融合抑制物T-1249(Trimeris)。我们建议：研究项目I：Robin Shattock， 进入抑制物在人类宫颈和直肠组织模型以及树突状细胞中的特征； 研究项目II：卡尔·马尔科姆，艾滋病毒-I类进入抑制剂的实用配方；研究项目III： 罗纳德·维兹，在猕猴身上测试实用杀菌剂；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 以及马克·米奇尼克(粒子科学公司)，他将参与研究项目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，也是在合作协议下。粒子科学的参与实现了 拟议研究计划的强制企业要素。如果此应用程序成功通过对等审查 并得到美国国立卫生研究院的支持，杀微生物剂国际伙伴关系将 提供支持沙托克博士领导的研究项目所需的大部分资金， Robbiani和Wolinsky，如申请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.