Polypeptide Microbicides Targeting CCR5

靶向 CCR5 的多肽杀菌剂

• 批准号: 6534391
• 负责人: ROBERT C GALLO
• 金额: $ 136.88万
• 依托单位: UNIVERSITY OF MD BIOTECHNOLOGY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-28 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534391
• 关键词: AIDS therapy; antiAIDS agent; antiviral agents; drug design /synthesis /production; gene targeting; synthetic peptide

Unprotected sexual intercourse accounts for the vast majority of new HIV infections worldwide. A disproportionate number of these infections occur in women due to a variety of physiological and behavioral factors. The severity of this problem begs for the development of safe and effective chemical barriers ("topical microbicides") women can use to prevent mucosal HIV infection. Important insights for the development of topical microbicides can be derived from biological determinants for sexual HIV transmission. Three lines of evidence point to the HIV coreceptor, CCR5, is one of the most important. First, CCR5 is well represented on the mucosal epithelial and is the major coreceptor used to enter resident cells. In accordance, the majority of sexually transmitted HIV strains use this coreceptor for infection. Second, the genetic loss of CCR5 is correlated with strong natural resistance to infection. Notably, there is no apparent health consequence associated with the loss of CR5. Third, the natural capacity of certain individuals to produce high levels of HIV-suppressive CCR5. Third, the natural capacity of certain individuals to produce high levels CCR5 ligands correlates with uninfected status despite repeated exposure to HIV. In accordance, primate vaccine studies have correlated increased chemokine production with protection from virus challenge. Based on these findings, our central hypothesis is that effective vaginal microbicides can be based on biological molecules that block the CCR5 entry coreceptor for HIV. To evaluate our hypothesis, we will attempt to block vaginal R5 SHIV infection of rhesus macaques with microbicide formulations consisting of a CCR5 ligand/HIV inhibitor suspended in a carrier vehicle. We will examine two candidate microbicides, each with a distinct set of potentially beneficial features, first for in vitro anti-viral activity and for safety in animal models. Once characterized, they will then be tested for efficacy in the macaque infection model. One formulation will incorporate the -2 isoform of RANTES, a natural and selective CCR5 ligand with potent HIV- suppressive activity, and the second another natural CCR5 ligand, the HIVgp120-CD4 receptor complex formed during HIV attachment. The antiviral component of this formulation will be an immunoadhesin based on our single chain gp120-CD4 chimeric polypeptide, which we recently provided to be a specific inhibitor of R5 HIV infection. Each formulation will use a type of non-phospholipid liposome (Novasomes) that has appeared to be safe for vaginal application in our preliminary studies. This work will be accomplished within the context of three straightforward and synergistic projects. Upon completing this program we expect to have produced at least one candidate vaginal microbicide capable of preventing vaginal infection by a CCR5-tropic SHIV that will have practical utility in humans.

无保护的性交是全世界绝大多数新的艾滋病毒感染。由于各种生理和行为因素，女性发生了这些感染的数量不成比例。该问题的严重程度乞求开发安全有效的化学障碍（“局部菌心”）女性可以用来防止粘膜HIV感染。开发局部微生物的重要见解可以从性别HIV传播的生物决定因素中得出。三条证据表明HIV共肽CCR5是最重要的。首先，CCR5在粘膜上皮上很好地表示，并且是用于进入居民细胞的主要共肽。根据据此，大多数性传播的艾滋病毒菌株都使用这种共感染者进行感染。其次，CCR5的遗传丧失与对感染的强烈自然抗性相关。值得注意的是，CR5的丧失没有明显的健康后果。第三，某些人的自然能力产生高水平的HIV抑制CCR5。第三，尽管反复接触HIV，但某些人产生高水平CCR5配体的自然能力与未感染的状态相关。根据趋势，灵长类动物疫苗的研究将趋化因子产生的增加与免受病毒挑战的保护相关。基于这些发现，我们的中心假设是有效的阴道微生物可以基于阻断HIV的CCR5进入共肽的生物分子。为了评估我们的假设，我们将尝试阻止猕猴的阴道R5 SHIV感染，该猕猴的猕猴具有杀菌剂制剂，该制剂由悬挂在载体车辆中的CCR5配体/HIV抑制剂组成。我们将检查两个候选菌皮，每个杀菌剂具有一组不同的潜在有益特征，首先用于体外抗病毒活性和动物模型的安全性。一旦表征，它们将在猕猴感染模型中测试功效。一种配方将结合rantes的-2同工型，一种具有有效的HIV活性的天然和选择性CCR5配体，第二个天然CCR5配体是HIV附着期间形成的HIVGP120-CD4受体复合物。该配方的抗病毒成分将是一种基于我们的单链GP120-CD4嵌合多肽的免疫粘附素，我们最近将其作为R5 HIV感染的特定抑制剂。每种配方将使用一种非磷脂脂质体（Novasomes），在我们的初步研究中似乎对阴道应用是安全的。这项工作将在三个直接和协同的项目的背景下完成。完成该程序后，我们希望至少产生一种候选阴道杀菌剂，能够通过CCR5 - 胶质SHIV预防阴道感染，该SHIV将在人类中具有实用性。