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: 8469159
• 负责人: JOHN P MOORE
• 金额: $ 28.68万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8469159
• 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申请是对RFA Al-07-001的回应，包含三个研究项目，一个科学核心和一个行政核心，由主要研究者John P.摩尔博士和共同主要研究者Robin A指导。Shattock博士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，旨在促进基于HIV-1进入抑制剂单独和/或联合应用的阴道杀微生物剂的开发。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。重点将是开发和评估长效杀微生物剂制剂和递送方法，例如控释阴道环，其可以在施用单一装置后的数周/数月内原位提供连续和恒定的活性化合物供应，以及可以每天施用一次或甚至更少频率的半固体制剂。我们将研究的抑制剂包括但可能不限于：小分子CCR抑制剂CMPDi 67（Merck）;小分子附着抑制剂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：研究项目一：Robin Shattock，人类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-1进入抑制剂的实用配方;研究项目III：罗纳德维泽，在猕猴中测试实用杀微生物剂;病毒学和免疫学核心：John P.摩尔;行政核心：John P.摩尔。该团队的其他高级成员包括Melissa Robbiani和Mark Mitchnick（Particle Sciences，Inc），他们将分别根据合作协议参与研究项目I和III，Steven Wolinsky将根据合作协议参与病毒学和免疫学核心。粒子科学的参与实现了拟议研究计划的强制性企业元素。如果该申请成功通过同行评审并获得NIH的支持，国际杀微生物剂伙伴关系将提供所需的大部分资金，以支持由Shattock，Robbiani和Wolinsky博士领导的研究计划，如申请的计划概述部分所述。 项目1：人宫颈和直肠组织模型中的进入抑制剂和树突状细胞的表征（PI Shattock，Robin J.） 项目1描述（由申请方提供）：已明确确定杀微生物剂在预防HIV-1粘膜传播中的潜在作用。然而，对候选杀微生物剂进行严格的临床前评价对于选择最佳化合物进行临床试验至关重要，因为考虑到正式疗效试验的费用和时间长度，这最终将节省成本和时间。最近失败或停止的III期试验（COL-1492，SAVVY和硫酸纤维素）突出了对使用不完全优化的杀微生物剂候选物进行功效试验的关注;这些试验表明，有效杀微生物剂的开发和配制可能不像最初想象的那样容易。虽然单核细胞培养物和动物模型可以为杀微生物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，它们可能无法充分模拟人体粘膜组织中发生的事件。因此，杀微生物剂候选物的临床前开发的综合计划需要从几个不同的模型系统中积累信息。因此，Shattock博士和Robbiani博士的研究小组已经开发了HIV-1感染人类粘膜组织和树突状细胞驱动的HIV-1传播的最早期事件的体外模型。这些模型非常适合测试旨在阻断HIV-1性传播的药剂的效力，并已广泛用于评估潜在的杀微生物剂候选物。此外，本文所述的实验以及与项目III中所述实验的交叉验证，可以确定有效性、安全性和依从性的潜在生物标志物，这些生物标志物可以为未来的临床试验提供信息。在本项目中，我们将使用这些已建立的模型来评估HIV-1进入抑制剂（单独和组合）及其制剂的有效性和相容性。这项研究将受到核心A内开展的工作的影响和指导，并将涉及与领导研究项目II和III的科学家的广泛互动和合作。不同组之间的相互作用将导致最有希望的抑制剂组合和制剂的快速跟踪，用于在猕猴模型中进行评价（研究项目III）。

项目成果

Non-aqueous silicone elastomer gels as a vaginal microbicide delivery system for the HIV-1 entry inhibitor maraviroc.

• DOI: 10.1016/j.jconrel.2011.08.006
• 发表时间: 2011-12-10
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Forbes CJ;Lowry D;Geer L;Veazey RS;Shattock RJ;Klasse PJ;Mitchnick M;Goldman L;Doyle LA;Muldoon BC;Woolfson AD;Moore JP;Malcolm RK
• 通讯作者: Malcolm RK

C-C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors.

• DOI: 10.1099/vir.0.025270-0
• 发表时间: 2010-12
• 期刊: The Journal of general virology
• 作者: Hu Q;Huang X;Shattock RJ
• 通讯作者: Shattock RJ

Modified silicone elastomer vaginal gels for sustained release of antiretroviral HIV microbicides.

• DOI: 10.1002/jps.23913
• 发表时间: 2014-05
• 期刊: JOURNAL OF PHARMACEUTICAL SCIENCES
• 影响因子: 3.8
• 作者: Forbes, Claire J.;Mccoy, Clare F.;Murphy, Diarmaid J.;Woolfson, A. David;Moore, John P.;Evans, Abbey;Shattock, Robin J.;Malcolm, R. Karl
• 通讯作者: Malcolm, R. Karl

The entry inhibitor DS003 (BMS-599793): a BMS-806 analogue, provides superior activity as a pre-exposure prophylaxis candidate.

• DOI: 10.1097/qad.0000000000002974
• 发表时间: 2021-10-01
• 期刊: AIDS (London, England)
• 作者: Herrera C;Harman S;Aldon Y;Rogers P;Armanasco N;Ziprin P;Stieh D;Nuttall J;Shattock RJ
• 通讯作者: Shattock RJ

Pharmacokinetics and efficacy of a vaginally administered maraviroc gel in rhesus macaques.

• DOI: 10.1093/jac/dks422
• 发表时间: 2013-03
• 期刊: The Journal of antimicrobial chemotherapy
• 作者: R. Malcolm;Claire J. Forbes;L. Geer;R. Veazey;L. Goldman;P. Klasse;John P. Moore