Targeting RIPK3 in Flu-Associated Lung Injury

靶向 RIPK3 治疗流感相关肺损伤

基本信息

批准号：
10238084
负责人：
SIDDHARTH BALACHANDRAN
金额：
$ 78.93万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
依托单位国家：
美国
项目类别：
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/10238084
关键词：
Acute Adult Respiratory Distress Syndrome Affect Animals Antiviral Agents 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 Crystallization Data Disease Distal Drug Kinetics Epithelial 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 Inflammation Lung diseases Lytic Virus Mediating Mediator of activation protein Modeling Molecular Conformation Molecular Target Morbidity - disease rate Mus Mutation Necrosis Pathogenicity Pathology Pathway interactions Pharmaceutical Chemistry Phosphotransferases Pneumococcal Pneumonia Pneumonia Pre-Clinical Model Proteins Pyrimidine RIPK3 gene Regimen Reporting Research Personnel Rheumatoid Arthritis Safety 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 base cell type clinically relevant drug discovery flu genomic RNA high risk improved in vivo in vivo Model influenza virus strain inhibitor/antagonist kinase inhibitor lung injury mortality mouse model novel therapeutics pandemic disease pandemic influenza programs scaffold seasonal influenza sensor small molecule therapeutic development therapeutic evaluation therapeutic target treatment strategy viral resistance

项目摘要

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 万人死亡此外，仅在美国就有高毒力的 H5 和 H7 禽流感病毒株，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。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性宿主信号通路，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 是一种重要的介质。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。季节性和流行性 IAV 菌株都会触发 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值得注意的是，RIPK3 还介导或放大一系列 TNF-α 介导的慢性病变（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。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强调了即时转化。 UH15 系列治疗坏死性肺损伤以及随后引发的 ARDS 和肺炎的潜力我们提案的目标是迭代优化基于 UH15 的 IAV 菌株。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（Balachandran，Thomas）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。