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.

无保护的性交占全世界艾滋病毒新感染的绝大多数。由于各种生理和行为因素，这些感染中不成比例的数量发生在妇女中。这一问题的严重性要求开发安全有效的化学屏障（“局部杀微生物剂”），妇女可以用来预防粘膜HIV感染。局部杀微生物剂的发展的重要见解可以来自性传播艾滋病毒的生物决定因素。有三条证据表明，HIV辅助受体CCR 5是其中最重要的一条。首先，CCR 5在粘膜上皮上有很好的代表性，并且是用于进入驻留细胞的主要辅助受体。因此，大多数性传播的HIV病毒株使用这种辅助受体进行感染。第二，CCR 5的遗传丢失与对感染的强天然抗性相关。值得注意的是，没有明显的健康后果与CR 5的损失有关。第三，某些个体产生高水平HIV抑制性CCR 5的天然能力。第三，某些个体产生高水平CCR 5配体的天然能力与未感染状态相关，尽管反复暴露于HIV。因此，灵长类动物疫苗研究将增加趋化因子的产生与保护免受病毒攻击相关联。基于这些发现，我们的中心假设是有效的阴道杀微生物剂可以基于阻断HIV的CCR 5进入辅助受体的生物分子。为了评估我们的假设，我们将试图阻止阴道R5 SHIV感染恒河猴与杀微生物剂配方组成的CCR 5配体/HIV抑制剂悬浮在载体车辆。我们将研究两种候选杀微生物剂，每一种都具有一组独特的潜在有益特征，首先是体外抗病毒活性和动物模型中的安全性。一旦表征，然后将在猕猴感染模型中测试它们的功效。一种制剂将掺入RANTES的-2同种型，一种具有有效HIV抑制活性的天然和选择性CCR 5配体，第二种是另一种天然CCR 5配体，在HIV附着期间形成的HIVgp 120-CD 4受体复合物。该制剂的抗病毒组分将是基于我们的单链gp 120-CD 4嵌合多肽的免疫粘附素，我们最近提供了R5 HIV感染的特异性抑制剂。每种制剂将使用一种非磷脂脂质体（Novasomes），在我们的初步研究中，这种脂质体似乎对阴道应用是安全的。这项工作将在三个直接和协同项目的范围内完成。在完成该项目后，我们期望已经产生至少一种候选的阴道杀微生物剂，其能够预防由CCR 5嗜性SHIV引起的阴道感染，其将在人类中具有实际效用。