RANTES Peptides

RANTES肽

• 批准号: 6809150
• 负责人: PAULO LUSSO
• 金额: $ 21.64万
• 依托单位: OSEL, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6809150
• 关键词: HIV infections; Lactobacillus; Macaca nemestrina; antiAIDS agent; bacterial genetics; biotechnology; biotherapeutic agent; calcium flux; chemokine; chemokine receptor; chemotaxis; communicable disease control; communicable disease transmission; cooperative study; drug design /synthesis /production; drug vehicle; human immunodeficiency virus 1; nonhuman therapy evaluation; topical drug application; vagina

According to the currently accepted model, HIV sequentially interacts with two cellular receptors, CD4 and a chemokine receptor. Although several chemokine receptors have been identified, only CCR5 and CXCR4 play a major role as HIV-1 coreceptors. In particular CCR5 is the most widely used coreceptor among HIV-1 isolates. RANTES, MIP-lalpha and MIP-lbeta selectively bind to CCR5 and this binding makes RANTES a potent natural inhibitor of HIV-1. However, the potential therapeutic use of this chemokine has been limited due to the risk of inducing inflammatory side effects or of interfering with the natural physiology of the chemokine system. Recently, evidence has been provided that the functional domain(s) of the chemokines that block HIV infection could be uncoupled from the signaling activity, making this domain(s) a potential template for the design of an effective HIV-coreceptor inhibitor devoid of unwanted inflammatory side-effects. The goal of this project is to combine the potentially powerful anti-HIV activity of RANTES analogs with Osel's Lactobacillus expression technology, to provide a continuous supply of HIV inhibitors at the vaginal mucosa. Specifically, we propose to employ a naturally-occurring vaginal strain of Lactobacillus to express secreted RANTES analogs. We will identify the most potent and selective Lactobacillus-expressed RANTES-based HIV inhibitor, stably integrate its expression cassette into the bacterial chromosome, conduct an in vivo safety and colonization study in the pig-tailed macaque with the selected recombinant Lactobacillus strain, and determine the in situ expression levels of the secreted RANTES analog. Finally, we propose to conduct an efficacy study in the pig-tailed macaque model to determine whether the lactobacillus-expressed RANTES analog can prevent viral transmission following intravaginal infection with SHIV.

根据当前接受的模型，HIV依次与两个细胞受体CD4和趋化因子受体相互作用。尽管已经鉴定出了几种趋化因子受体，但仅CCR5和CXCR4作为HIV-1共感受器起主要作用。特别是CCR5是HIV-1分离株中使用最广泛的共肽。 rantes，mip-lalpha和mip-lbeta选择性地结合了CCR5，这种结合使rantes成为HIV-1的有效天然抑制剂。但是，由于诱导炎症副作用或干扰自然生理学的风险，这种趋化因子的潜在治疗使用受到限制 趋化因子系统。最近，已经提供了证据表明，趋化因子的功能结构域可以与信号活性中阻断HIV感染，从而使该结构域成为设计有效的HIV受体抑制剂，没有不需要的炎症副作用的潜在模板。 该项目的目的是将RANTES类似物的潜在强大抗HIV活性与Osel的乳杆菌表达技术相结合，以在阴道粘膜上连续供应HIV抑制剂。具体而言，我们建议使用乳酸杆菌的天然阴道菌株表达分泌的rantes类似物。我们将确定最有效，最有选择的基于Rantes的HIV HIV抑制剂，稳定地将其表达盒与细菌染色体结合到细菌染色体中，在小猪尾猕猴中与所选重组的乳杆菌菌株中进行体内安全和殖民研究，并确定原位的表达水平。最后，我们建议在猪尾猕猴模型中进行疗效研究，以确定乳酸杆菌表达的rantes类似物是否可以防止用SHIV进行玻璃体内后感染后的病毒传播。