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.

抽象的 有效的联合抗逆转录病毒疗法 (cART) 的出现延长了 HIV-1 的预期寿命 然而，这些患者仍然容易出现合并症，例如与艾滋病毒相关的神经认知障碍 疾病 (HAND)，影响高达 50% 的 HIV 感染者。由于持续的炎症 先天免疫系统的过度激活是 HAND 的主要原因之一。核苷酸结合 结构域，富含亮氨酸的重复热蛋白结构域含有蛋白 3 (NLRP3) 炎性体已成为 用于治疗 HIV-1 相关神经病理学的药物靶点。 NLRP3 炎症小体是 显示出对多种病原体和危险相关分子模式的反应而被激活 （分别为 PAMP 和 DAMP）。激活过程中的一个关键步骤是之间的同型相互作用 NLRP3 中的热蛋白结构域和接头蛋白（含有 CARD 的凋亡相关斑点样蛋白） （ASC）。 NLRP3 激活导致促炎细胞因子的释放，例如白介素-1 (IL-1) 和 IL-18，导致神经元焦亡和死亡。通过小分子破坏 NLRP3 信号传导，例如 据报道，MCC950 在转基因小鼠模型中显示出有益的作用。我们最近的研究发现 一种小分子 AMS-17，在体内和体外都能阻止 N9 小胶质细胞中 NLRP3 的激活。 随后的机制分析表明，AMS-17 的 NLRP3 抑制活性归因于其能力 结合NLRP3热蛋白结构域，从而阻止NLRP3和ASC之间的相互作用。这个提议是 专注于开发具有改善的生物活性、低毒性和高药物相似性的AMS-17类似物。 本提案中描述的目标 1 重点关注计算机辅助设计、合成和化学 AMS-17 类似物的表征。目标 2 将涉及在人源化小鼠中测试主要候选药物 手的模型。拟议的研究非常重要，因为它们将为以下疾病提供新的治疗选择： 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业知识： 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）。它与本次 RFA 的目标完全一致，有望定义 NLRP3 抑制 化合物通过不同于任何其他目前使用的药物的新颖机制发挥作用。