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

• 批准号: 10454494
• 负责人: PAUL Anthony WENDER
• 金额: $ 79.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454494
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adverse effects; Animal Model; Anti-Retroviral Agents; Biodistribution; Cells; Cellular biology; Chemicals; Clinical; Comparative Study; Computers; Disease Progression; Dose; Drug or chemical Tissue Distribution; Drug toxicity; Effector Cell; Esters; Evaluation; Family; Goals; Grant; HIV; HIV Infections; HIV Seropositivity; Health; Histone Deacetylase; Immune; In Vitro; Individual; Infection; Laboratories; Libraries; Life; Medical; NF-kappa B; Natural Killer Cells; Noise; Pathway interactions; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plant Roots; Plasma; Prodrugs; Protein Isoforms; Protein Kinase C; Protein Kinase C Inhibitor; Proviruses; Publications; Regimen; Resistance; Safety; Science; Series; Signal Pathway; Source; Testing; Therapeutic Intervention; Toxic effect; Transcriptional Activation; Viral Cytopathogenic Effect; Viral load measurement; Viral reservoir; Virus; Virus Latency; Work; analog; antiretroviral therapy; base; benzotriazole; bryostatin; clinically relevant; cost; cytokine; design; humanized mouse; improved; in vitro Assay; in vivo; in vivo Model; inhibitor/antagonist; mimetics; mouse model; novel; pre-clinical; prostratin; protein farnesyltransferase; research clinical testing; synergism; targeted treatment; transcriptomics; viral resistance; virology

ABSTRACT Although anti-retroviral therapy (ART) slows disease progression, ART is a life-long therapy, which requires strict medical compliance to avoid viral resistance and is associated with significant costs and long-term medically adverse effects. In addition, ART is not curative because it does not eliminate reservoirs of replication-competent virus. Thus, if ART is discontinued, HIV can emerge from reservoirs and rapidly spread, leading to disease progression towards AIDS. One potential strategy for clearing these reservoirs of latently infected cells is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, allowing their subsequent “killing” by viral cytopathic effects, immune effector cells or additional therapies targeted at HIV-infected cells. Latency reversing agents (LRA) have been used to “kick” or induce HIV expression from latent cells, but thus far have been limited by suboptimal efficacy, drug toxicity, and/or biodistribution issues. In this renewal application, we address these problems using a new LRA concept to improve efficacy and tolerability and control biodistribution. We investigate protein kinase C (PKC) modulators, which are the most potent and efficacious LRAs, focusing particularly on the best-performers - bryostatin-1, prostratin and ingenol esters and potentially new LRAs of the ingenane and tigliane families. We have found that the chemical conversion of bryostatin-1 into a prodrug (slow-release) version results in a novel LRA with superior activity and improved tolerability. Thus, the goal of this renewal application is to advance the study of this new concept and new class of chemically synthesized prodrug LRAs using a highly collaborative team with expertise in novel computer-based design, synthesis, medicinal chemistry, state-of-the-art in vitro assays, and sophisticated in vivo animal modeling. Optimal prodrug LRAs will be used in conjunction with a “kill” approach (natural killer cells) in humanized mice latently infected with HIV to assess the efficacy of the kick and kill approach. We will accomplish our goals through the following Specific Aims: 1) Evaluate in vitro and in vivo a new concept for latency reversal based on new LRA prodrugs, 2) Define the specific PKC isoforms and non-PKC pathways that contribute to HIV latency reversal, and 3) Investigate synergies of new and known LRAs that enhance HIV reservoir depletion. Collectively these studies will advance our unique and superior preclinical LRAs towards clinical testing and provide information critically needed for implementation of kick and kill approaches for HIV eradication.

抽象的 尽管抗逆转录病毒治疗（ART）可以减缓疾病进展，但ART是一种终生治疗，需要严格的治疗 医疗依从性以避免病毒耐药性，并且与巨大的成本和长期的医疗相关 不良影响。此外，ART 没有治疗作用，因为它不能消除具有复制能力的病毒库。 病毒。因此，如果停止抗逆转录病毒治疗，艾滋病毒可能会从储存库中出现并迅速传播，导致疾病 艾滋病的进展。清除这些潜伏感染细胞库的一种潜在策略是使用 一种踢杀方法，其中潜伏细胞被“踢出”或从潜伏期激活，从而允许它们随后 通过病毒细胞病变效应、免疫效应细胞或针对 HIV 感染细胞的其他疗法来“杀死”。 潜伏逆转剂 (LRA) 已被用来“踢”或诱导潜伏细胞表达 HIV，但迄今为止 受到次优功效、药物毒性和/或生物分布问题的限制。在这份续签申请中， 我们使用新的 LRA 概念来解决这些问题，以提高功效、耐受性和控制 生物分布。我们研究蛋白激酶 C (PKC) 调节剂，它们是最有效的 LRA，特别关注表现最好的药物 - 苔藓抑素-1、前列腺素和巨大戟二萜醇酯，以及潜在的 ingenane 和 tigliane 家族的新 LRA。我们发现苔藓抑素-1化学转化为 前药（缓释）版本产生了具有卓越活性和改善耐受性的新型 LRA。因此， 此更新应用程序的目标是推进对这一新概念和新类别化学的研究 使用具有新型计算机设计专业知识的高度协作团队合成前药 LRA， 合成、药物化学、最先进的体外测定和复杂的体内动物模型。 最佳前药 LRA 将与“杀死”方法（自然杀伤细胞）结合用于人源化小鼠 潜伏感染艾滋病毒的人来评估踢杀方法的功效。我们将实现我们的目标 通过以下具体目标：1）在体外和体内评估基于潜伏期逆转的新概念 新的 LRA 前药，2) 定义导致 HIV 潜伏期的特定 PKC 亚型和非 PKC 途径 逆转，以及 3) 研究新的和已知的 LRA 的协同作用，以增强 HIV 储存库的耗竭。集体 这些研究将推动我们独特且卓越的临床前 LRA 走向临床测试，并提供 实施消灭艾滋病毒的踢杀方法急需的信息。