Polypeptide Microbicides Targeting CCR5

靶向 CCR5 的多肽杀菌剂

• 批准号: 6443774
• 负责人: ROBERT C GALLO
• 金额: $ 74.23万
• 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/6443774
• 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.

无保护措施的性行为占全球新增艾滋病毒感染的绝大多数。由于各种生理和行为因素，这些感染中有不成比例的数量发生在女性身上。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”)，妇女可以使用这些屏障来预防粘膜艾滋病毒感染。可以从艾滋病毒性传播的生物学决定因素中获得开发局部杀微生物剂的重要见解。有三条证据表明，HIV辅助受体CCR5是最重要的之一。首先，CCR5在粘膜上皮细胞上有良好的表达，是进入驻留细胞的主要辅助受体。因此，大多数性传播的艾滋病毒毒株都使用这种辅助受体来感染。其次，CCR5的遗传缺失与其对感染的天然抵抗力强有关。值得注意的是，CR5的缺失没有明显的健康后果。第三，某些人产生高水平抑制艾滋病毒的CCR5的天然能力。第三，尽管反复接触艾滋病毒，某些人产生高水平CCR5配体的自然能力与未感染状态相关。根据灵长类疫苗的研究，增加趋化因子的产生与保护免受病毒攻击有关。基于这些发现，我们的中心假设是，有效的阴道杀菌剂可以基于阻止HIV的CCR5进入共受体的生物分子。为了验证我们的假设，我们将尝试用悬浮在载体载体中的CCR5配体/HIV抑制剂组成的杀微生物剂配方来阻止恒河猴经阴道感染R5SHV。我们将检查两种候选的杀菌剂，每种都有一套不同的潜在有益特征，首先是体外抗病毒活性和动物模型中的安全性。一旦确定了特征，它们将在猕猴感染模型中进行有效性测试。一种配方将包含RANTES的-2异构体，这是一种天然的、选择性的CCR5配体，具有强大的艾滋病毒抑制活性；第二种配方将包括另一种天然CCR5配体，即在HIV附着过程中形成的HIVgp120-CD4受体复合体。该配方的抗病毒成分将是基于我们的单链gp120-CD4嵌合多肽的免疫粘附素，我们最近提供了这种多肽作为R5 HIV感染的特异性抑制剂。每种制剂都将使用一种非磷脂脂质体(Novasome)，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的项目范围内完成。在完成这项计划后，我们希望生产出至少一种候选的阴道杀菌剂，能够预防CCR5嗜性SIV的阴道感染，这将对人类具有实用价值。