Recombinant CCR5 Inhibitors for Topical Microbicides

用于局部杀菌剂的重组 CCR5 抑制剂

• 批准号: 7174060
• 负责人: DONALD E MOSIER
• 金额: $ 23.1万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7174060
• 关键词: AIDS; Africa; Macaca; chemical synthesis; clinical research; disease outbreaks; enzymes; infection; inflammation; lead; local antiinfective agents; model; phage display; proteins; recombinant proteins; temperature; topical drug application

DESCRIPTION (provided by applicant): This R21/R33 Phased Innovation Award application proposes to develop novel RANTES derivatives capable of recombinant expression as candidate topical microbicides. These molecules target the CCR5 coreceptor used by HIV-1 isolates responsible for primary transmission. Two lead candidates with antiviral activity against CCR5-using HIV-1 isolates equivalent to the fully synthetic PSC-RANTES have been identified using an innovative phage display selection process that allows screening of millions of CCR5 binding molecules. One of these molecules shares the inhibitory mechanism of PSC-RANTES, CCR5 internalization and sequestration, and also shares signaling activity via CCR5. The second molecule, although equally potent at inhibiting virus infection, does not cause CCR5 internalization or signaling via CCR5. These properties could improve the safety profile of this molecule. The objectives of the R21 phase of the proposal are to determine the mechanism of activity of the two molecules, the duration of activity after compound removal, and the activity against clade A, C, and D primary transmission isolates from sub- Saharan Africa. We will also attempt to generate resistant variants to both molecules in vitro, and compare the stability of the molecules to low pH, high temperature, and exposure to cervicovaginal lavage (CVL) fluid. The molecule with the best combination of properties in these experiments will be selected for preclinical evaluation in the R33 phase using the SHIV162P3 vaginal challenge model in female rhesus macaques. These experiments will establish the effective dose for preventing transmission, determine if that dose protects against delayed virus challenge, and evaluate local inflammation and induction of proinflammatory cytokines as indicators of safety. Virus recovered from treated animals with delayed viremia will be evaluated for development of resistance to the lead RANTES derivative. These studies are designed to lead to a safe, effective, and inexpensive protein CCR5 inhibitor for incorporation into a topical microbicide for use in areas most impacted by the global HIV/AIDS pandemic.

描述（由申请人提供）：此R21/R33分阶段创新奖的申请提出了开发能够重组表达作为候选局部杀菌剂的新型Rantes衍生物。这些分子靶向负责主要传播的HIV-1分离株使用的CCR5共肽。使用创新的噬菌体显示选择过程，已经鉴定出了与完全合成PSC统计相当的CCR5使用HIV-1分离株具有抗病毒活性的两名铅候选者，该候选物可以筛选数百万个CCR5结合分子。这些分子之一具有PSC-rantes，CCR5内在化和隔离的抑制作用机制，还通过CCR5共享信号传导活性。第二个分子虽然在抑制病毒感染方面同样有效，但不会通过CCR5引起CCR5内在化或信号传导。这些特性可以改善该分子的安全性。该提案的R21阶段的目标是确定两个分子的活性机理，化合物去除后的活性持续时间以及针对A，C和D进化枝A，C和D的活性分离了来自撒哈拉以南非洲的非洲。我们还将尝试在体外对两个分子产生抗性变体，并比较分子与低pH值，高温和暴露于子宫颈阴道灌洗（CVL）流体的稳定性。这些实验中具有最佳性质组合的分子将在雌性恒河猕猴中使用SHIV1623阴道挑战模型在R33期中选择临床前评估。这些实验将建立防止传播的有效剂量，确定该剂量是否可以防止病毒挑战延迟，并评估局部炎症并诱导促炎细胞因子作为安全指标。从治疗的动物延迟病毒血症中回收的病毒将被评估，以发展对铅衍生物的抗性。这些研究旨在导致一种安全，有效且廉价的蛋白CCR5抑制剂掺入局部菌心，以在受全球HIV/AIDS大流行影响最大的区域使用。