Towards HIV eradication: New concepts and potent compounds for PKC-mediated latency reversal

消灭 HIV：PKC 介导的潜伏期逆转的新概念和有效化合物

基本信息

批准号：
10652684
负责人：
PAUL Anthony WENDER
金额：
$ 79.78万
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：
2022
资助国家：
美国
起止时间：
2022-07-20 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10652684
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Address Animal Model Anti-Retroviral Agents Area Biodistribution Cells Cellular biology Chemicals Clinical Comparative Study Computers Disease Progression Dose Drug or chemical Tissue Distribution Effector Cell Esters Evaluation Family Generations Goals HIV HIV Infections HIV antiretroviral Health Histone Deacetylase Immune In Vitro Individual Infection Interruption Laboratories Libraries Life Mediating NF-kappa B Natural Killer Cells Noise Persons Pharmaceutical Chemistry Pharmaceutical Preparations Plant Roots Plasma Prodrugs Protein Isoforms Protein Kinase C Protein Kinase C Inhibitor Proviruses Publishing Regimen Reporting Resistance Science Signal Pathway Source Structure Testing Therapeutic Therapeutic Intervention Toxic effect Transcriptional Activation Viral Cytopathogenic Effect Viral load measurement Viral reservoir Virus Virus Latency Work analog antiretroviral therapy base benzotriazole bryostatin cost cytokine design humanized mouse improved in vitro Assay in vivo in vivo Model inhibitor mimetics mouse model next generation novel pre-clinical preclinical development programs prostratin protein farnesyltransferase purge research clinical testing scaffold synergism targeted treatment transcriptomics virology

项目摘要

ABSTRACT Although anti-retroviral therapy (ART) slows disease progression, ART is a life-long therapy. Significantly, ART is not curative. It does not eliminate reservoirs of replication-competent virus. Thus, when ART is discontinued, HIV emerges from reservoirs and rapidly spreads, leading to disease progression towards AIDS. One strategy for clearing these reservoirs of latently infected cells, the principal if not sole source of continued infection, is to use a kick and kill approach, in which latent cells are “kicked” or activated from latency, allowing their subsequent “killing” or clearance by viral cytopathic effects, immune effector cells or additional therapies targeted at HIV- infected cells. To this end, we show proof-of-concept that a kick and kill strategy with uniquely effective latency reversing agents (LRA) and NK cells remarkably targets the HIV reservoir in a humanized mouse model, leading to a milestone of treatment interruption. Our next goal is to further enhance our kick and kill components to eradicate all replication-competent reservoirs of virus present during ART. We will design, synthesize, and investigate promising new compounds, the best kick components uncovered thus far, with the overall goal of producing superior LRAs and synergistic strategies that efficiently and safely purge the latent HIV in vivo. LRAs have been used to induce HIV expression from latent cells, but thus far have been limited by suboptimal efficacy, tolerability issues, and/or biodistribution concerns. Here, we address these problems using new LRA concepts and structures to improve efficacy, tolerability and control biodistribution. We investigate protein kinase C (PKC) modulators, which are the most potent and efficacious LRAs reported thus far. Within this family we have identified the best performers yet reported, inspired by bryostatin-1, prostratin and ingenol esters and new LRA scaffolds of the ingenane, tigliane, and epoxy-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 (60% v. 98%) and significantly improved tolerability (20-fold increase in therapeutic window). Thus, our goal is to advance this study of these new LRAs and chemically synthesized prodrugs 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. To move this program toward clinical entry, optimal LRAs and prodrugs 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 strategy. We will accomplish our goals through the following Specific Aims: 1) Evaluate in vitro and in vivo new generation latency reversal agents based on new LRA scaffolds and their prodrugs, representing the most effective and best tolerated LRAs reported thus far, 2) Define and selectively activate PKC isoforms that enhance HIV latency reversal and improve tolerability, and 3) Develop new synergistic strategies to deplete the HIV reservoir. Collectively these studies will advance our unique and superior preclinical LRAs towards clinical testing.

抽象的尽管抗逆转录病毒疗法（ART）减慢了疾病的进展，但ART是一种终生的疗法。重要的是，艺术无法治愈。它不会消除复制能力的病毒的水库。当艺术停产时，艾滋病毒从水库中出现并迅速传播，导致疾病向艾滋病的发展。一种策略为了清除这些储层的潜在感染细胞，主感染的主要根源是使用踢和杀死方法，其中潜在细胞被“踢”或从延迟中激活，允许其后续序列病毒细胞病毒作用，免疫效应细胞或针对HIV-的其他疗法的“杀死”或清除感染细胞。为此，我们表明了概念证明，踢和杀死策略具有独特的有效延迟逆转剂（LRA）和NK细胞在人源化小鼠模型中明显靶向HIV储存剂达到治疗中断的里程碑。我们的下一个目标是进一步增强我们的踢脚和杀死组件消除艺术期间存在的所有具有复制能力的储层。我们将设计，合成，并且调查承诺新化合物，这是迄今为止发现的最佳踢零件，其总体目标是生产出色的LRA和协同策略，可有效，安全地清除体内潜伏的HIV。 lras 已被用于诱导潜在细胞的HIV表达，但到目前为止，受到次优效率的限制，耐受性问题和/或生物分布问题。在这里，我们使用新的LRA概念解决了这些问题以及提高效率，耐受性和控制生物分布的结构。我们研究了蛋白激酶C（PKC）调节剂，这是迄今为止报告的最潜在和有效的LRA。在这个家庭中，我们有确定了迄今为止表现最好的人，灵感来自Bryostatin-1，Prstratin和Ingenol酯以及新的LRA Ingenane，Tigliane和环氧植被家族的脚手架。我们发现 Bryostatin-1进入前药（慢速释放）版本会导致具有出色活性的新型LRA（60％v。98％）和显着提高了耐受性（治疗窗口增加了20倍）。那是我们的目标是推进这项研究在这些新的LRA和化学合成的前药中，有一个高度协作的团队具有小说专业知识基于计算机的设计，合成，药物化学，最先进的体外测定和体内精致动物建模。为了将该程序转向临床进入，最佳LRA和前药将用于与人性化小鼠中的“杀伤”方法（自然杀伤细胞）的结合，被艾滋病毒感染，以评估踢和杀死战略的功效。我们将通过以下特定目标来实现我们的目标：1）根据新的LRA支架及其前药，代表到目前为止报道的最有效，最耐受的LRA，2）定义和选择性地定义激活PKC同工型，以增强HIV潜伏期逆转并提高耐受性，3）开发新的破坏艾滋病毒水库的协同策略。这些研究集体将推进我们独特的和临床上的临床前LRA进行临床测试。