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：
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
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/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

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.

项目摘要/摘要季节性流感病毒（IAV）感染占70万住院和50,000年死亡此外在人类之间，只有少数突变获得了广泛的传播能力当前的疫苗和抗病毒策略要么受到限制，要么容易受到病毒恢复的影响逃避，确定针对季节性和病毒IAV疾病的新的治疗切入点，最好是目标致病宿主信号通路是紧急的势力。尽可能多地为AS的中央介体A的中央介体A的中央介体高度促炎的细胞死亡形式称为坏死性，我们发现这也是主要贡献者 IAV感染期间的肺损伤和炎症。我们提出的依赖性坏死肺损害，急性呼吸窘迫综合征（ARDS）以及病毒和逆性性肺炎，每种肺炎都是死亡的主要原因 IAV感染。作为类风湿关节炎），使其具有多种炎症状况的新分子靶标。奇怪的是，考虑到治疗靶标RIPK3的重要性可能是多么重要，没有选择性RIPK3抑制剂具有已进入临床试验。调用UH15系列，并基于pyrido [2,3-D]嘧啶支架，该嘧啶脚手架均针对ATP-AS 以及我们的初步发现的同种异性ripk3。一轮优化，比当前的RIPK3抑制剂更有效，并且表现出有希望的活动 IAV在体外和体内诱导坏死。 UH15系列的坏死性肺肺肺的潜力以及肺炎和肺炎触发。 IAV的季节性和病毒性菌株。 RIPK3在体外进行阻断的化合物，并通过使用RIPK3介导的病理的快速小鼠模型（The） TNF SIRS模型），优先使用用于体内的组合（AIM 1）。在各种AV触发疾病环境中具有治疗功效的化合物，包括（1）的情景高风险的季节性IAV感染，（2）高度致病的鸟类IAV感染和（3）次级肺炎季节性IAV感染后的肺炎（AIM 2）。具有强大的小分子药物化学（CUNY）的互补专业知识在IAV发病机理期间，炎症（Degterev）和RIPK3介导的细胞死亡信号传导中的功能和功能（Balachandran，Thomas）。由坏死肺肺肺部引发或扩增多种IAV诱导的疾病。