Targeting RIPK3 in Flu-Associated Lung Injury

靶向 RIPK3 治疗流感相关肺损伤

• 批准号: 10689229
• 负责人: SIDDHARTH BALACHANDRAN
• 金额: $ 70.2万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10689229
• 关键词: Acute; Acute Respiratory Distress Syndrome; Affect; Animals; Apoptosis; Area; Avian Influenza A Virus; Bacterial Pneumonia; Binding; Biochemistry; Biological Assay; Birds; Cell Death; Cell Death Signaling Process; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Complex; Curiosities; Data; Disease; Distal; Drug Kinetics; Epithelium; Goals; Hospitalization; Human; In Vitro; Infection; Inflammation; Inflammatory; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Injury; Laboratories; Lead; Lung; Lung diseases; Lytic Virus; Mediating; Mediator; Modeling; Molecular Conformation; Molecular Target; Morbidity - disease rate; Mus; Mutation; Necrosis; Necrosis Induction; Pathogenicity; Pathology; Pathway interactions; Pharmaceutical Chemistry; Phosphotransferases; Pneumococcal Pneumonia; Pneumonia; Pre-Clinical Model; Predisposition; Proteins; Pulmonary Inflammation; Pyrimidine; RIPK3 gene; Regimen; Reporting; Research Personnel; Rheumatoid Arthritis; Safety; Seasons; Series; Signal Pathway; Structure; Structure-Activity Relationship; Systemic Inflammatory Response Syndrome; TNF gene; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Vaccines; Viral; Viral Pathogenesis; Viral Pneumonia; Virulent; Virus; Virus Diseases; airway epithelium; analog; appropriate dose; cell type; clinically relevant; drug discovery; fascinate; flu; genomic RNA; high risk; improved; in vivo; in vivo Model; influenza virus strain; inhibitor; kinase inhibitor; lung injury; mortality; mouse model; novel therapeutic intervention; novel therapeutics; pandemic disease; pandemic influenza; programs; scaffold; seasonal influenza; sensor; small molecule; therapeutic development; therapeutic evaluation; therapeutic target; translational potential; viral resistance

PROJECT SUMMARY/ABSTRACT Seasonal influenza A virus (IAV) infections account for over 700,000 hospitalizations and 50,000 annual deaths in the US alone. Moreover, highly virulent H5 and H7 strains of avian IAV, while currently limited in their spread between humans, are only a few mutations from acquiring the capacity for widespread transmissibility. As current vaccines and antiviral strategies are either limited in their efficacy or susceptible to viral resistance and evasion, identifying new therapeutic entry-points for seasonal and virulent IAV disease, preferably those that target pathogenic host signaling pathways, is an urgent imperative. We have identified the host kinase RIPK3 as a promising new entry point for therapeutic development against IAV. RIPK3 is the central mediator of a highly pro-inflammatory form of cell death termed necroptosis, which we have found is a major contributor to lung injury and inflammation during IAV infection. Both seasonal and pandemic strains of IAV trigger RIPK3- dependent necrotic lung damage that we propose underlies Acute Respiratory Distress Syndrome (ARDS), as well as viral and bacterial pneumonia, each of which remain major causes of morbidity and mortality following IAV infection. Notably, RIPK3 also mediates or amplifies a range of chronic TNF-α-mediated pathologies (such as rheumatoid arthritis) making it a very attractive new molecular target for multiple inflammatory conditions. Curiously, given how important a therapeutic target RIPK3 potentially is, no selective RIPK3 inhibitors have been advanced into clinical trials. We now have developed a new structural class of RIPK3 inhibitor, which we call the UH15 series, and which is based on a pyrido[2,3-d]pyrimidine scaffold that targets both the ATP- as well as the allosteric Glu-out pockets of RIPK3. Our preliminary findings reveal that UH15 analogs, after just one round of optimization, are already more potent than current RIPK3 inhibitors and display promising activity against IAV induced necrosis in vitro and in vivo. These exciting results highlight the immediate translational potential of the UH15 series for necrotic lung injury and consequent ARDS and pneumonia triggered by seasonal and virulent strains of IAV. The goals of our proposal are to iteratively optimize UH15-based compounds for RIPK3 blockade in vitro and, by use of a rapid mouse model of RIPK3-mediated pathology (the TNF SIRS model), prioritize compounds for use in vivo (Aim 1). We then propose to assess these UH15 compounds for therapeutic efficacy in a variety of IAV-triggered disease settings, including the scenarios of (1) high-risk seasonal IAV infections, (2) infection by highly pathogenic avian IAV, and (3) secondary pneumococcal pneumonia following seasonal IAV infection (Aim 2). The proposed studies bring together a team of researchers with strong, complementary expertise in small-molecule medicinal chemistry (Cuny), RIPK3 kinase biochemistry and function in inflammation (Degterev), and RIPK3-mediated cell death signaling during IAV pathogenesis (Balachandran, Thomas). Successful completion of these Aims has the potential to transform the treatment of multiple IAV-induced diseases initiated or amplified by necrotic lung injury.

项目概要/摘要 季节性甲型流感病毒 (IAV) 感染每年导致超过 70 万人住院和 5 万人死亡 仅在美国。此外，禽流感病毒 H5 和 H7 株具有高毒力，但目前其传播受到限制 人类之间，只有少数突变才能获得广泛传播的能力。作为 当前的疫苗和抗病毒策略要么功效有限，要么容易受到病毒耐药性的影响 逃避，确定季节性和致命性 IAV 疾病的新治疗切入点，最好是那些 靶向致病宿主信号通路，已是当务之急。我们已经确定了宿主激酶 RIPK3 作为 IAV 治疗开发的一个有前景的新切入点。 RIPK3 是一个中枢介导者 高度促炎的细胞死亡形式称为坏死性凋亡，我们发现它是导致细胞死亡的主要原因 IAV 感染期间的肺损伤和炎症。 IAV 的季节性和大流行株都会触发 RIPK3- 我们认为，依赖性坏死性肺损伤是急性呼吸窘迫综合征 (ARDS) 的基础，因为 以及病毒性和细菌性肺炎，这两种肺炎仍然是发病和死亡的主要原因 甲型肝炎病毒感染。值得注意的是，RIPK3 还介导或放大一系列 TNF-α 介导的慢性病理（例如 如类风湿性关节炎）使其成为治疗多种炎症性疾病的非常有吸引力的新分子靶点。 奇怪的是，考虑到 RIPK3 潜在治疗靶点的重要性，目前尚无选择性 RIPK3 抑制剂 已进入临床试验阶段。我们现在开发了一种新结构的 RIPK3 抑制剂，我们将其 称为 UH15 系列，它基于吡啶并[2,3-d]嘧啶支架，同时靶向 ATP- 以及 RIPK3 的变构 Glu-out 口袋。我们的初步研究结果表明，UH15 类似物，仅在 经过一轮优化，已经比目前的 RIPK3 抑制剂更有效，并显示出有前景的活性 抗 IAV 诱导的体外和体内坏死。这些令人兴奋的结果凸显了即时转化 UH15 系列治疗坏死性肺损伤以及随后引发的 ARDS 和肺炎的潜力 IAV 的季节性和强毒株。我们提案的目标是迭代优化基于 UH15 的 体外阻断 RIPK3 的化合物，并通过使用 RIPK3 介导的病理学快速小鼠模型（ TNF SIRS 模型），优先考虑体内使用的化合物（目标 1）。然后我们建议评估这些 UH15 在各种 IAV 引发的疾病环境中具有治疗功效的化合物，包括 (1) 的情况 高危季节性 IAV 感染，(2) 高致病性禽 IAV 感染，以及 (3) 继发性肺炎球菌 季节性 IAV 感染后出现肺炎（目标 2）。拟议的研究汇集了一组研究人员 在小分子药物化学 (Cuny)、RIPK3 激酶生物化学方面拥有强大、互补的专业知识 炎症和功能 (Degterev)，以及 IAV 发病过程中 RIPK3 介导的细胞死亡信号传导 （巴拉钱德兰，托马斯）。成功完成这些目标有可能改变治疗方法 由坏死性肺损伤引发或放大的多种 IAV 诱发的疾病。