HIV latency reversal through novel, potent PKC modulators

通过新型、有效的 PKC 调节剂逆转 HIV 潜伏期

基本信息

批准号：
9136468
负责人：
PAUL Anthony WENDER
金额：
$ 64.54万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9136468
关键词：
Address Animal Model Biodistribution Biological Assay Blood Cells Cancer Patient Cell Death Cell Line Cells Characteristics Chemistry Clinical Clinical Trials Clinical assessments Collection Comparative Study Disease Progression Dose Drug Delivery Systems Enrollment Flushing Future HIV Health Histone Deacetylase Histone Deacetylase Inhibitor Human immunodeficiency virus test Immune In Vitro Individual Infection Kinetics Laboratories Latent Virus Libraries Life Mediating Modeling Mus Natural Products Noise Organism Patients Pharmaceutical Preparations Pharmacology Phase Plant Roots Plasma Prodrugs Protein Kinase C Proviruses Reagent Series Shock Signal Pathway Source Techniques Testing Therapeutic Intervention Time Toxic effect Transcriptional Activation Viral Viral Antigens Viral Cytopathogenic Effect Viral load measurement Viral reservoir Virus Work analog antiretroviral therapy base benzotriazole bryostatin comparative cytokine cytotoxicity design humanized mouse improved in vivo Model inhibitor/antagonist killings marine organism nonhuman primate novel pre-clinical prostratin protein farnesyltransferase public health relevance research clinical testing scaffold scale up simian human immunodeficiency virus synthetic protein virology

项目摘要

DESCRIPTION (provided by applicant): While antiretroviral therapy (ART) has been effective in stopping or slowing disease progression for most HIV infected individuals, it is not curative. ART must instead be continuous for life, requires strict compliance, is costly, and is implicated i numerous health problems attributed to long-term chemo-exposure. Eradication of the virus would address these problems, however this has proven extremely difficult. One potential means of reducing or eliminating HIV reservoirs is to administer agents to flush the virus out of hiding while on ART, which should induce death of the cell either by virus-mediated cytotoxicity, or immune-mediated clearance. Alternatively, additional reagents specific for newly expressed viral antigens could be administered to complete this "kick and kill" strategy. Protein kinase C (PKC) modulators are among the most active HIV latency reversing agents identified to date. However, natural PKC modulators have inherent toxicities and sub-optimal potencies. This proposal brings together several laboratories with relevant expertise in chemistry, virology and animal modeling, to advance the study of synthetic PKC modulators with reduced toxicities and improved latency reversal activities through a suite of pre-clinical assessments. We will scale-up synthesis of several (already identified) improved PKC modulators, and create novel slow release versions of these compounds with the potential to further reduce toxicities. We will subject these molecules to in vitro assessment of activity in various assays including primary cells from patients on suppressive ART, and perform in vivo modeling of latency reversal in humanized mice. This in turn will inform proposed pharmacology and efficacy studies in non-human primates. Together the studies proposed herein will provide important information regarding kick and kill approaches for HIV eradication, and advance these unique and superior compounds towards clinical testing.

描述（由申请人提供）：虽然抗逆转录病毒疗法 (ART) 可以有效阻止或减缓大多数 HIV 感染者的疾病进展，但 ART 并不能治愈，而是必须终生持续，需要严格依从，费用昂贵且效果不佳。根除病毒可以解决这些问题，但事实证明，减少或消除艾滋病毒储存库的一种潜在方法是使用药物清除病毒。 ART 期间的隐藏，这应该通过病毒介导的细胞毒性或免疫介导的清除诱导细胞死亡。或者，可以施用针对新表达的病毒抗原的其他试剂来完成这种“踢杀”策略。激酶 C (PKC) 调节剂是迄今为止发现的最活跃的 HIV 潜伏期逆转剂之一，然而，天然 PKC 调节剂具有固有的毒性和次优效力。该提案汇集了多个具有化学、病毒学相关专业知识的实验室。和动物模型，通过一系列临床前合成评估来推进具有降低毒性和改善潜伏期逆转活性的合成 PKC 调节剂的研究，我们将扩大几种（已确定的）改进的 PKC 调节剂的规模，并创建新型缓释剂。我们将在各种试验中对这些化合物的活性进行体外评估，包括来自抑制性 ART 患者的原代细胞，并在人源化小鼠中进行潜伏期逆转的体内建模。反过来，将为非人类灵长类动物的药理学和功效研究提供信息，本文提出的研究将提供有关根除 HIV 的踢杀方法的重要信息，并推动这些独特且优越的化合物走向临床测试。