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.

全球新发艾滋病毒感染绝大多数是由无保护的性交造成的。由于各种生理和行为因素，这些感染在女性中发生的比例不成比例。这个问题的严重性要求开发安全有效的化学屏障（“局部杀菌剂”），供女性用来预防粘膜艾滋病毒感染。开发局部杀菌剂的重要见解可以从艾滋病毒性传播的生物决定因素中得出。三个证据表明 HIV 辅助受体 CCR5 是最重要的之一。首先，CCR5 在粘膜上皮上有很好的表现，并且是用于进入常驻细胞的主要辅助受体。因此，大多数通过性传播的 HIV 毒株都使用这种辅助受体进行感染。其次，CCR5 的遗传缺失与对感染的强大自然抵抗力相关。值得注意的是，CR5 的缺失不会对健康造成明显的后果。第三，某些个体产生高水平的 HIV 抑制性 CCR5 的自然能力。第三，尽管反复接触HIV，某些个体产生高水平CCR5配体的自然能力与未感染状态相关。因此，灵长类疫苗研究将趋化因子产生的增加与免受病毒攻击的保护联系起来。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 CCR5 进入辅助受体的生物分子。为了评估我们的假设，我们将尝试使用由悬浮在载体中的 CCR5 配体/HIV 抑制剂组成的杀菌剂制剂来阻断恒河猴的阴道 R5 SHIV 感染。我们将研究两种候选杀菌剂，每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。一旦鉴定完毕，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亚型（一种具有有效HIV抑制活性的天然选择性CCR5配体）和另一种天然CCR5配体，即HIV附着期间形成的HIVgp120-CD4受体复合物。该制剂的抗病毒成分是基于我们的单链 gp120-CD4 嵌合多肽的免疫粘附素，我们最近将其作为 R5 HIV 感染的特异性抑制剂。每种配方都将使用一种非磷脂脂质体（Novasomes），在我们的初步研究中，这种脂质体对于阴道应用似乎是安全的。这项工作将在三个简单且协同的项目的背景下完成。完成该计划后，我们预计将生产出至少一种候选阴道杀微生物剂，能够预防 CCR5 嗜性 SHIV 引起的阴道感染，并将在人类中具有实际用途。