Developing RANTES analogues as topical strategies to prevent HIV transmission

开发 RANTES 类似物作为预防 HIV 传播的局部策略

基本信息

批准号：
7418081
负责人：
MICHAEL MARCEL LEDERMAN
金额：
$ 30.18万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-06-06 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418081
关键词：
AIDS prevention Address Agonist Animals Antiviral Agents Antiviral Therapy Attenuated Bypass C-Type Lectins CCR5 gene CD4 Positive T Lymphocytes Cervical Characteristics Collaborations Communication Data Development Diffusion Dose Drug Formulations Effectiveness Elements Endopeptidases Exposure to Fermentation Food Fuzeon Guanosine Monophosphate HIV HIV Infections Hand Hour Human Hydrogels Immunity Immunologics In Vitro Infection Inflammation Inflammatory Inflammatory Response Injectable Lactobacillus Lead Macaca mulatta Male Circumcision Manufacturer Name Mediating Methods Modeling Numbers Pathway interactions Peptide Hydrolases Phage Display Polyethylene Glycols Prevention strategy Price Production Proteins Publishing RANTES RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-Recombinant RANTES Recombinants Research Risk Seminal Signal Pathway Solutions Sterility System Techniques Testing Time Tissues Topical application Update Vaccines Vagina Virus Diseases analog attenuation base bovine growth hormone chemical synthesis chemokine cost cytokine design experience farmer microbicide nonhuman primate novel pandemic disease pre-clinical prevent protective effect rectal research study safety net simian human immunodeficiency virus size transmission process vector

AIDS prevention Address Agonist Animals Antiviral Agents Antiviral Therapy Attenuated Bypass C-Type Lectins CCR5 gene CD4 Positive T Lymphocytes Cervical Characteristics Collaborations Communication Data Development Diffusion Dose Drug Formulations Effectiveness Elements Endopeptidases Exposure to Fermentation Food Fuzeon Guanosine Monophosphate HIV HIV Infections Hand Hour Human Hydrogels Immunity Immunologics In Vitro Infection Inflammation Inflammatory Inflammatory Response Injectable Lactobacillus Lead Macaca mulatta Male Circumcision Manufacturer Name Mediating Methods Modeling Numbers Pathway interactions Peptide Hydrolases Phage Display Polyethylene Glycols Prevention strategy Price Production Proteins Publishing RANTES RANTES, N(alpha)-(n-nonanoyl)-desSer(1)-(thioproline(2),cyclohexylglycine(3))-Recombinant RANTES Recombinants Research Risk Seminal Signal Pathway Solutions Sterility System Techniques Testing Time Tissues Topical application Update Vaccines Vagina Virus Diseases analog attenuation base bovine growth hormone chemical synthesis chemokine cost cytokine design experience farmer microbicide nonhuman primate novel pandemic disease pre-clinical prevent protective effect rectal research study safety net simian human immunodeficiency virus size transmission process vector

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项目摘要

Project 3: There is no proven microbicide strategy, and recent large scale trials have failed to show protection. While there are numerous strategies in the pipeline for development, it is essential that promising strategies be explored, as none to date have succeeded and each strategy in development has some potential drawbacks and challenges. Our group has successfully demonstrated the plausibility of targeting CCR5 using modified RANTES analogues as a strategy to prevent mucosal transmission of HIV infection. While these seminal studies have helped to revise the paradigm of topical prevention strategies, there remain several potential obstacles to the application of amino terminus modified RANTES analogues as topical strategies to prevent mucosal transmission of HIV infection. Many of these potential obstacles are shared by other topical HIV prevention strategies that have been proposed. The potential challenges to these strategies include: potential agonist activity of some RANTES analogues, potency, durability of effect, and cost. Thus Project #3 of this collaborative application will attempt to resolve these limitations with the following specific aims: Sp Aim #1: to determine the signaling pathways that mediate the induction of inflammatory cytokines by PSC-RANTES (and other RANTES analogues) in vaginal/cervical tissue and to disrupt these signaling pathways as a mechanism to reduce the inflammatory responses to RANTES analogues while preserving anti-HIV activity. Sp. Aim #2: to evaluate the antiviral activities (and immunologic effects) of combination strategies that may provide additive or synergistic antiviral protection together with RANTES analogues. Sp. Aim #3: to explore novel hydrogel formulation strategies that may permit more durable intravaginal exposure to RANTES analogues and other compounds. Sp. Aim #4: to develop methods for the high scale GMP grade synthesis of recombinant RANTES analogues (6P4-RANTES, and 5P12-RANTES, and 5P14-RANTES - fully recombinant agents that are as active in vitro as PSC-RANTES in terms of HIV inhibition) that will permit affordable application of this topical prevention strategy. Successful completion of these studies by this experienced team will likely result in clarifying the pathways to development of this promising strategy for topical prevention of HIV transmission.

项目3：没有经过验证的杀微生物策略，最近的大规模试验未能显示保护。尽管有许多策略的发展策略，但必须有希望探索策略，因为迄今为止还没有成功，并且每种制定策略都有一些潜在的缺点和挑战。我们的小组成功证明了目标的合理性 CCR5使用改良的Rantes类似物作为防止HIV感染粘膜传播的策略。尽管这些开创性研究有助于修改局部预防策略的范式，但仍然是应用氨基末端修改的rantes类似物的几个潜在障碍防止艾滋病毒感染的粘膜传播的局部策略。这些潜在的许多障碍是已提出的其他局部艾滋病毒预防策略共享。潜在的挑战这些策略包括：某些类似物的潜在激动活动，效力，效果耐用性，和成本。因此，此协作应用程序的项目＃3将尝试通过以下方式解决这些限制具体目的： SP AIM＃1：确定介导通过阴道/宫颈组织中的PSC-rantes（和其他rantes类似物），并破坏这些信号途径是减少对Rantes类似物的炎症反应的机制抗HIV活性。 sp。目标＃2：评估可能可能与Rantes类似物一起提供添加剂或协同的抗病毒保护。 sp。目的＃3：探索新型水凝胶配方策略，这些策略可能允许更耐用的静脉内暴露于类似物和其他化合物。 sp。目标＃4：开发重组rantes的高度GMP级合成的方法类似物（6p4驱动器和5p12驱动器和5p14-rantes-完全重组剂在艾滋病毒抑制方面，活跃的体外作为PSC统计预防策略。这个经验丰富的团队成功完成这些研究可能会导致澄清开发这种有前途的策略的途径，用于预防HIV传播。