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：
10700404
负责人：
PAUL Anthony WENDER
金额：
$ 46.91万
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：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10700404
关键词：
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/AIDS 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 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 Virus Replication Work analog antiretroviral therapy benzotriazole bryostatin chemical synthesis cost cytokine design efficacy evaluation 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) 可以减缓疾病进展，但 ART 是一种终生疗法。它不能消除具有复制能力的病毒库，因此，当停止 ART 时，艾滋病毒从储存库中出现并迅速传播，导致疾病进展为艾滋病。为了清除这些潜伏感染细胞的储存库，持续感染的主要来源（如果不是唯一来源）是使用踢杀方法，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 的其他疗法“杀死”或清除为此，我们展示了一种具有独特有效潜伏期的踢杀策略。逆转剂 (LRA) 和 NK 细胞专门针对人源化小鼠模型中的 HIV 储存库，我们的下一个目标是进一步增强我们的踢杀组件，以实现治疗中断的里程碑。我们将设计、合成和根除 ART 期间存在的所有具有复制能力的病毒库。研究有前途的新化合物，迄今为止发现的最好的踢球成分，总体目标是生产卓越的 LRA 和协同策略，有效、安全地清除体内潜伏的 HIV。已被用于诱导潜伏细胞的 HIV 表达，但迄今为止仍受到次优功效的限制，耐受性问题和/或生物分布问题在这里，我们使用新的 LRA 概念来解决这些问题。我们研究了蛋白激酶 C (PKC)。调节剂，这是迄今为止我们在该家族中报道的最有效的 LRA。受到苔藓抑素-1、前列腺素和巨大戟二萜醇酯以及新 LRA 的启发，确定了迄今为止报道的最佳表现我们发现了六烯烷、替利亚烷和环氧-替利亚烷家族的化学转化。将苔藓抑素-1 转化为前药（缓释）版本可产生具有优异活性的新型 LRA（60% vs. 98%）显着提高耐受性（治疗窗增加 20 倍）因此，我们的目标是推进这项研究。这些新的 LRA 和化学合成的前药使用具有新颖专业知识的高度协作团队基于计算机的设计、合成、药物化学、最先进的体外测定和复杂的体内分析为了使该计划走向最佳临床阶段，LRA 和前药将用于与潜伏感染 HIV 的人源化小鼠中的“杀死”方法（自然杀伤细胞）相结合，以评估我们将通过以下具体目标实现我们的目标：1) 评估基于新型 LRA 支架的体外和体内新一代潜伏期逆转剂及其前药，代表迄今为止报道的最有效和最好耐受的 LRA，2) 定义和选择性激活 PKC 同工型，增强 HIV 潜伏期逆转并提高耐受性，以及 3) 开发新的总的来说，这些研究将推动我们独特和有效的消灭艾滋病毒储存库的协同策略。优于临床前 LRA 进行临床测试。