Acute Inhibition of TAK1 as a Means to Control COVID-19 Pulmonary Hyperinflammation

急性抑制 TAK1 作为控制 COVID-19 肺部高炎症的方法

• 批准号: 10458667
• 负责人: TIMOTHY A HAYSTEAD
• 金额: $ 28.47万
• 依托单位: EYDIS BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458667
• 关键词: 2019-nCoV; Acute; Acute Respiratory Distress Syndrome; Adverse reactions; Alveolar; Animal Model; Animals; Anti-Inflammatory Agents; Anti-Tumor Necrosis Factor Therapy; Antiinflammatory Effect; Antiviral Agents; Autoimmune Diseases; Biological; Biological Products; COVID-19; COVID-19 complications; COVID-19 cytokine storm; COVID-19 pandemic; COVID-19 patient; COVID-19 treatment; COVID-19/ARDS; Cell Nucleus; Cells; Cessation of life; Characteristics; Chronic; Chronic Disease; Clinical; Clinical Data; Clinical Trials; Cytokine Signaling; Data; Development; Disease; Disease Outcome; Disease Progression; Dose; Edema; Elements; Fibrosis; Funding; Future; Health; Healthcare Systems; Herd Immunity; Human; Immune; Immune response; Immune system; Immunomodulators; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Injectable; Interleukin-1; Interleukin-6; Intervention; Invaded; Lung; MAP Kinase Gene; Mediating; Mediator of activation protein; Middle East Respiratory Syndrome Coronavirus; Modeling; Molecular; Natural Immunity; Nuclear; Oral; Outcome; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Physiological; Pneumonia; Prevention; Protein Kinase; Proteins; Public Health; Pulmonary Challenge; Quality of Care; Regimen; Respiratory Disease; Rheumatoid Arthritis; Risk; Role; Route; SARS coronavirus; SARS-CoV-2 infection; SARS-CoV-2 spike protein; Severity of illness; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; TNF gene; Therapeutic; Time; Transforming Growth Factor beta; Treatment Efficacy; Tumor Necrosis Factor Receptor; United States National Institutes of Health; Vaccines; Viral; Virus; Virus Diseases; Work; acquired immunity; base; chemokine; comorbidity; cost; cytokine; cytokine release syndrome; efficacy testing; human model; improved; in vivo; infection risk; inflammatory marker; inhibitor; innovation; macrophage; neutrophil; novel; novel coronavirus; novel therapeutic intervention; novel therapeutics; p38 Mitogen Activated Protein Kinase; pandemic disease; pathogen; pathogen exposure; pathogenic bacteria; pathogenic virus; pre-clinical; prevent; pulmonary function; response; scaffold; side effect; small molecule inhibitor; small molecule therapeutics; targeted treatment; therapeutic target; therapy development; treatment optimization; treatment strategy; viral detection

PROJECT SUMMARY/ABSTRACT The recent pandemic of novel coronavirus, COVID-19, has had a devastating effect on the health and well-being of individuals across the globe, including over 3.1 million confirmed infected so far, and a monumental impact on global healthcare systems and economies at large. In the US, over 1,000,000 cases have been confirmed to date, including over 60,000 deaths, and some studies estimate that COVID-19 could cost the US healthcare system $556 billion over the next two years. There are currently no approved treatments for COVID-19, and many current efforts are expectedly targeting the viral mechanisms of disease. However, evidence from COVID- 19 patients has identified hyperinflammation as a major contributor to disease progression and outcomes, and reduction of hyperinflammatory mediators such as TNF, IL-1 and IL-6 has become a novel therapeutic axis for the treatment of COVID-19 patients. Thus, various branded anti-cytokine immunomodulators (e.g., anti-IL-1 and anti-IL-6 biologics) are currently undergoing clinical trials to treat complications of COVID-19 disease such as acute respiratory distress syndrome (ARDS), cytokine release syndrome, and pneumonia. However, all of these therapeutics remove all target cytokine expression, dampening immune-viral detection leading to disease progression. Therefore, there exists an unmet need for an orally bioavailable small molecule therapeutic that can taper inflammatory cytokines to normal levels in an active COVID-19 infection. Our preclinical work has identified TGFβ-activated kinase 1 (TAK1), as a key signaling element within the TNF-mediated proinflammatory response pathway. Given recent clinical data identifying TNF as the primary player in the initiation of the COVID-19 induced cytokine storm, we posit that TAK1 can be targeted to prevent or greatly reduce pulmonary hyperinflammation seen in COVID-19 patients. Our recent discovery of the takinib scaffold and subsequent medicinal chemistry efforts have led to the development of the first orally bioavailable, highly selective and potent (IC50 ~2.5nM) inhibitor of TAK1, HS-276. To obtain proof-of-concept for development of TAK1 as target for COVID-19 induced ARDS, we propose the following Specific Aims: Aim 1 – Establish the therapeutic efficacy of HS-276 to reduce inflammation in the LPS-induced pulmonary inflammatory model. Milestone: Define the therapeutic window of HS-276 in the LPS-induced pulmonary inflammatory model. Aim 2 – Evaluate the in vitro and in vivo effects of TAK1 inhibition with HS-276 in response to COVID-19 spike protein (S-protein) challenge. Milestone: Establish that HS-276 blocks S-protein induced TNF expression by ≥50% compared to vehicle-treated in vitro. Aim 3 – Determine the efficacy of HS-276 to reduce viral-induced ARDS in a SARS-CoV-2 model. Milestone: Expand preclinical indication/efficacy data of HS-276 to treat viral induced pulmonary hyperinflammation. Achieving the Specific Aims above will provide the necessary data for us to pursue a Phase II NIH SBIR application to fund pre-IND-enabling studies en route to IND-enabling studies.

项目摘要/摘要 新型冠状病毒Covid-19的最近大流行对健康和福祉造成了毁灭性影响 全球个人的个人，包括迄今为止已有310万个确认的感染，以及每月影响 关于全球医疗保健系统和整个经济。在美国，已确认超过100万例 日期，包括超过60,000人死亡，一些研究估计Covid-19可能会使美国医疗保健造成 系统在未来两年内为5560亿美元。目前尚无对COVID-19的批准治疗，以及 当前的许多努力预计针对疾病的病毒机制。但是，来自共同的证据 19例患者已确定高脑膜化是疾病进展和结局的主要贡献者，以及 降低高炎性介质（例如TNF，IL-1和IL-6）已成为一种新型治疗轴 COVID-19患者的治疗。那是各种品牌的抗循环反应免疫调节剂（例如，抗IL-1和 抗IL-6生物制剂目前正在接受临床试验，以治疗199疾病的并发症，例如 急性呼吸窘迫综合征（ARDS），细胞因子释放综合征和肺炎。但是，所有这些 治疗消除了所有靶因子表达，该死的免疫病毒检测导致疾病 进展。因此，存在未满足的口服生物利用的小分子疗法的需求 在活跃的COVID-19感染中，锥度炎症细胞因子达到正常水平。我们确定的临床前工作 TGFβ激活激酶1（TAK1），作为TNF介导的促炎反应中的关键信号传导元件 路径。鉴于最新的临床数据将TNF识别为启动Covid-19引起的主要参与者 细胞因子风暴，我们肯定可以将TAK1靶向以防止或大大减少肺动脉症 在199位患者中可见。我们最近发现了高尼脚手架和随后的医学化学 努力导致了第一个口头生物利用，高度选择性和潜力的发展（IC50〜2.5nm） TAK1的抑制剂，HS-276。为了获得开发TAK1的概念证明，作为COVID-19的目标 ARDS，我们提出以下特定目的：目标1 - 建立HS-276的治疗效率以减少 LPS诱导的肺部炎症模型中的炎症。里程碑：定义的治疗窗口 LPS诱导的肺炎症模型中的HS-276。 AIM 2 - 评估体外和体内影响 HS-276抑制TAK1响应Covid-19-Spike蛋白（S蛋白）挑战。里程碑：建立 与媒介物处理的体外，HS-276可阻断S蛋白诱导TNF表达≥50％。目标3 - 确定HS-276在SARS-COV-2模型中降低病毒诱导的ARDS的效率。里程碑：扩展 HS-276的临床前指示/功效数据治疗病毒诱导的肺部高炎症。实现 上面的具体目标将为我们提供必要的数据，以追求II阶段NIH SBIR申请以资助 预先启用的研究在辅助研究的途径中。

项目成果

Investigation of SARS-CoV-2 individual proteins reveals the in vitro and in vivo immunogenicity of membrane protein.

• DOI: 10.1038/s41598-023-49077-2
• 发表时间: 2023-12-18
• 期刊: SCIENTIFIC REPORTS
• 影响因子: 4.6
• 作者: Haystead, Timothy;Lee, Eric;Cho, Kirstin;Gullickson, Gail;Hughes, Philip;Krafsur, Greta;Freeze, Robert;Scarneo, Scott
• 通讯作者: Scarneo, Scott