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

• 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
• 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

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：尚无行之有效的杀菌剂策略，最近的大规模试验也未能证明 保护。尽管有许多发展战略正在酝酿之中，但至关重要的是， 需要探索战略，因为迄今为止还没有成功的战略，而且制定中的每项战略都有一些 潜在的缺点和挑战。我们的团队已成功证明了目标定位的合理性 CCR5 使用修饰的 RANTES 类似物作为预防 HIV 感染粘膜传播的策略。 虽然这些开创性的研究有助于修正局部预防策略的范式，但 氨基末端修饰的 RANTES 类似物的应用仍然存在一些潜在障碍，如 预防艾滋病毒感染粘膜传播的局部策略。其中许多潜在的障碍是 与已提出的其他局部艾滋病毒预防策略相同。潜在的挑战 这些策略包括：一些 RANTES 类似物的潜在激动剂活性、效力、效果的持久性、 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 具体目标： Sp 目标 #1：确定介导炎症细胞因子诱导的信号通路 PSC-RANTES（和其他 RANTES 类似物）在阴道/宫颈组织中并破坏这些信号传导 途径作为一种机制，减少对 RANTES 类似物的炎症反应，同时保留 抗艾滋病毒活性。 Sp。目标#2：评估可能的联合策略的抗病毒活性（和免疫效果） 与 RANTES 类似物一起提供附加或协同的抗病毒保护。 Sp。目标#3：探索新的水凝胶配方策略，使阴道内更持久 接触 RANTES 类似物和其他化合物。 Sp。目标#4：开发大规模 GMP 级合成重组 RANTES 的方法 类似物（6P4-RANTES、5P12-RANTES 和 5P14-RANTES - 完全重组制剂，如 在 HIV 抑制方面与 PSC-RANTES 一样在体外具有活性），这将允许该局部应用的经济实惠的应用 预防策略。 这个经验丰富的团队成功完成这些研究可能会澄清 制定这一有前景的局部预防艾滋病毒传播策略的途径。