Development of NLRP3 inhibitors for HIV-associated neuroinflammation

开发治疗 HIV 相关神经炎症的 NLRP3 抑制剂

• 批准号: 10548568
• 负责人: MICHAEL Ilya BUKRINSKY
• 金额: $ 21.2万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10548568
• 关键词: Adaptor Signaling Protein; Affect; Antiviral Therapy; Apoptosis; Area; Astrocytes; Behavioral; Binding; Biochemical; Biological; Brain; CASP1 gene; Cell Line; Cessation of life; Chemicals; Chronic; Clinical Research; Computer Assisted; Computer-Aided Design; Dementia; Development; Drug Design; Drug usage; Exploratory/Developmental Grant; Foundations; Functional disorder; Future; Goals; HIV; HIV Infections; HIV-1; HIV-associated neurocognitive disorder; In Vitro; Individual; Infection; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interdisciplinary Study; Interleukin-1; Interleukin-18; Investigation; Lead; Leucine-Rich Repeat; Licorice; Life Expectancy; Mediating; Memory; Microglia; Modeling; Molecular; Neurocognitive; Neurons; Nucleotides; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Pattern; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Preclinical Drug Development; Process; Proteins; Publications; Reporting; Research; Role; Series; Signal Transduction; Structure; Sulfonylurea Compounds; TNF gene; Testing; Therapeutic; Toxic effect; Transgenic Mice; Translational Research; Virus Diseases; analog; antiretroviral therapy; base; chemical stability; comorbidity; computer studies; cytokine; cytokine release syndrome; drug development; drug discovery; druggable target; humanized mouse; improved; in vitro Assay; in vitro activity; in vitro testing; in vivo; in vivo evaluation; inhibitor; innovation; lead candidate; marenostrin; mouse model; neurocognitive disorder; neuroinflammation; neuron loss; neuropathology; novel; novel therapeutics; nucleotide receptor; pathogen; pharmacophore; preclinical development; prevent; response; screening; small molecule

ABSTRACT The advent of effective combination antiretroviral therapies (cART) has increased the life expectancy for HIV-1 patients, however, these patients are still prone to comorbidities, such as HIV-associatiated neurocognitive disorders (HAND), which affect up to 50% of HIV-infected individuals. Persistent inflammation due to the overactivation of the innate immune system is one of the main underlying causes of HAND. Nucleotide binding domain, leucine rich repeat pyrin domain containing protein-3 (NLRP3) inflammasome has emerged as a druggable target for the management of HIV-1-associated neuropathologies. The NLRP3 inflammasome is shown to be activated in response to a wide array of pathogen- and danger-associated molecular patterns (PAMPs and DAMPs, respectively). A key step in the activation process is a homotypic interaction between the pyrin domains in NLRP3 and an adapter protein, apoptosis-associated speck-like protein containing a CARD (ASC). NLRP3 activation leads to the release of pro-inflammatory cytokines, such as, interleukin-1 (IL-1) and IL-18, causing neuronal pyroptosis and death. Disruption of NLRP3 signaling via small molecules, such as MCC950, is reported to display beneficial effects in the transgenic mouse models. Our recent studies identified a small molecule, AMS-17, that thwarted the NLRP3 activation in N9 microglia both in vitro and in vivo. Subsequent mechanistic analysis revealed that the NLRP3 inhibitory activity of AMS-17 is attributed to its ability to bind to NLRP3 pyrin domain, thus preventing the interaction between NLRP3 and ASC. This proposal is focused on developing AMS-17 analogues with improved biological activity, low toxicity, and high drug-likeness. Aim 1 described in this proposal is focused on the computer-assisted design, synthesis and chemical characterization of AMS-17 analogues. Aim 2 will involve testing of the lead candidates in the humanized mouse model of HAND. The proposed studies are highly significant since they will provide new therapeutic options to minimize HIV-associated neurocognitive dysfunction. The proposal incorporates expertise in the area of synthetic medicinal chemistry (Dr. Kulkarni), biological screening (Dr. Bukrinsky), and computer-assisted drug design (Dr. Adzhubei). It is fully consistent with the goals of this RFA and is expected to define NLRP3 inhibitory compounds working through a novel mechanism different from that of any other currently used drug.

摘要 有效的联合抗逆转录病毒疗法（cART）的出现增加了HIV-1的预期寿命 然而，这些患者仍然倾向于合并症，如HIV相关的神经认知功能障碍。 这些疾病（HAND）影响高达50%的HIV感染者。持续性炎症是由于 先天免疫系统的过度激活是HAND的主要潜在原因之一。核苷酸结合 结构域，富含亮氨酸重复的pyrin结构域包含蛋白质-3（NLRP 3）炎性体已成为一种 治疗HIV-1相关神经病变的药物靶点。NLRP 3炎性小体是 显示其响应于广泛的病原体和细菌相关的分子模式而被激活 （分别为PAMP和DAMP）。激活过程中的关键步骤是细胞间的同型相互作用。 NLRP 3中的pyrin结构域和衔接蛋白，含有CARD的染色体易位相关斑点样蛋白 （ASC）。NLRP 3激活导致促炎细胞因子的释放，例如白细胞介素-1 β（IL-1 β）和 IL-18，导致神经元焦亡和死亡。通过小分子破坏NLRP 3信号传导，例如 据报道，MCC 950在转基因小鼠模型中显示出有益效果。我们最近的研究发现 一种小分子AMS-17，其在体外和体内均阻碍N9小胶质细胞中的NLRP 3活化。 随后的机制分析表明，AMS-17的NLRP 3抑制活性归因于其能力， 结合NLRP 3 pyrin结构域，从而阻止NLRP 3和ASC之间的相互作用。这项建议是 致力于开发生物活性更高、毒性更低、药物相似性更高的AMS-17类似物。 目标1是计算机辅助设计、合成和化学合成 AMS-17类似物的表征。目标2将涉及在人源化小鼠中测试先导候选物 手的模型。拟议的研究非常重要，因为它们将提供新的治疗选择， 最大限度地减少艾滋病毒相关的神经认知功能障碍。该提案纳入了以下领域的专门知识： 合成药物化学（Kulkarni博士）、生物筛选（Bukrinsky博士）和计算机辅助药物 设计（Adzhubei博士）。这与本RFA的目标完全一致，预计将定义NLRP 3抑制性 这些化合物通过不同于任何其他目前使用的药物的新机制起作用。