Discovery of Novel Anti-inflammatory, Non-immunosuppressive Molecules forMitigation of Cytokine Storm in COVID-19 Patients

发现新型抗炎、非免疫抑制分子，可缓解 COVID-19 患者的细胞因子风暴

• 批准号: 10482311
• 负责人: Mehran F Moghaddam
• 金额: $ 23.64万
• 依托单位: OROX BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10482311
• 关键词: Acute; Acute Lung Injury; Acute Respiratory Distress Syndrome; Adherence; Animal Model; Animals; Anti-Inflammatory Agents; Attenuated; Benchmarking; Biological; Biological Assay; Biological Sciences; COVID-19; COVID-19 morbidity; COVID-19 mortality; COVID-19 pandemic; COVID-19 patient; California; Cardiac; Cause of Death; Caymans; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chemicals; Collection; Cytokine Suppression; Data; Development; Dexamethasone; Disease; Early Intervention; Endothelial Cells; Enzyme Inhibition; Enzymes; Epidemiology; Epithelial Cells; Epoxide hydrolase; Fibroblasts; Fibrosis; Glucocorticoids; Goals; Head; Health; Human; Immunosuppression; In Vitro; Individual; Infection; Inflammatory; Lead; Letters; Logistics; Lung infections; Medical; Michigan; Microsomal Epoxide Hydrolase; Monoclonal Antibodies; Morbidity - disease rate; Multiple Organ Failure; Mus; Neuraxis; Pathologic; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Policies; Population; Preparation; Prevention; Process; Production; Pulmonary Fibrosis; Reporting; SARS-CoV-2 infection; Safety; Small Business Innovation Research Grant; Source; Steroids; Survivors; System; Testing; Therapeutic; Tissues; Translating; United States; Update; Vaccination; Viral; Viral Pathogenesis; Work; World Health Organization; Writing; assault; asymptomatic COVID-19; chemotherapy; coronavirus disease; counterscreen; cyclooxygenase 1; cyclooxygenase 2; cytokine; cytokine release syndrome; design; epidemiologic data; high throughput analysis; improved; in vitro Assay; in vivo; inhibitor; innovation; long-term sequelae; lung injury; macrophage; mortality; novel; novel coronavirus; novel drug class; pandemic disease; prevent; professor; prototype; remdesivir; severe COVID-19; side effect; single molecule; small molecule; small molecule libraries; vaccine access; vaccine hesitancy

Project Summary/Abstract The World Health Organization has reported over 216 million confirmed cases of COVID-19 infections and over 4.5 million deaths world-wide as of August 31, 2021. The rapid introduction of this new coronavirus into a previously unexposed (`naive') population has resulted in a pandemic with tragic consequences on a global scale. Although epidemiological data suggests that many individuals infected with COVID-19 are asymptomatic or resolve their infection, a significant number become seriously ill with dysregulated and excessive cytokine production that can result in a pathological condition termed Cytokine Storm (CS) or Cytokine Release Syndrome (or CRS). These results suggest that treatment of hyperinflammation to prevent cytokine storm could improve COVID-19 associated morbidity and mortality in severe cases. As of this writing, the therapeutic options such as monoclonal antibodies and remdesivir have questionable value, dexamethasone immunosuppression may be problematic in COVID-19 patients, and the available vaccine(s) will be limited by production, vaccination logistics and citizenry concerns and skepticism (so-called `vaccine hesitancy'). We therefore surmise that access to a drug with a low side-effect profile which is able to effectively control the cytokine storm, regardless of the stage of disease, remains a high unmet medical need. We intend to fill this gap with a novel class of drugs that will reduce both the morbidity and mortality associated with the cytokine storm. We have designed and synthesized novel small molecules that are `dual' inhibitors of soluble epoxide hydrolase (sEH) and selected secondary anti-inflammatory targets including cyclooxygenase-2 (COX-2). Given the involvement of these targets in inflammatory processes, we believe our molecules have the potential to mitigate A key innovation to be implemented as part of our strategy is to incorporate both inhibitory activities into a single molecule, in the form of that can effectively control hyperinflammation without global immunosuppression. Our lead dual inhibitor, PTUPB, was discovered and characterized by the head of our scientific advisory board, Professor Bruce Hammock (UC Davis, California). ARDS and hyperinflammation associated with COVID-19. dual sEH/COX-2 inhibitors, Recently, PTUPB was demonstrated to an effective suppressor of chemotherapy-induced cytokine storm. This work has demonstrated that in contrast to conventional anti- inflammatory drugs, this dual sEH/COX-2 inhibitors can prevent the cytokine storm without the accompanying immunosuppression that may result from use of a potent glucocorticoid such as dexamethasone. We hypothesize that our molecules can be used in early intervention, as opposed to steroids, to disrupt progression of COVID-19 disease and reduce mortality. We propose to 1) screen 50 of our novel molecules against sEH and COX-2 and identify a subset of molecules with a range of potencies against the targeted enzymes, and 2) screen that subset of molecules in unbiased high-throughput analyses to identify novel molecules with potential to prevent or ameliorate the cytokine storm.

项目总结/摘要 世界卫生组织报告了超过2.16亿例新冠肺炎确诊病例， 4.5截至2021年8月31日，全球死亡人数为100万人。这种新型冠状病毒迅速引入一个 以前未接触（“天真”）的人群导致了一场大流行，对全球造成了悲惨的后果。 规模尽管流行病学数据表明，许多COVID-19感染者没有症状， 或解决他们的感染，相当多的人患上了严重的疾病，细胞因子失调和过量 可导致称为细胞因子风暴（CS）或细胞因子释放综合征的病理状况的产生 (or CRS）。这些结果表明，治疗过度炎症以防止细胞因子风暴可以改善 严重病例中COVID-19相关的发病率和死亡率。在撰写本文时， 由于单克隆抗体和Remdesivir的价值值得怀疑， 在COVID-19患者中存在问题，并且可用的疫苗将受到生产，疫苗接种 后勤和公民的关切和怀疑（所谓的“疫苗犹豫”）。因此，我们认为， 涉及一种具有低副作用特征的药物，其能够有效地控制细胞因子风暴， 疾病的早期阶段，仍然是一个高度未满足的医疗需求。我们打算用一种新型药物来填补这一空白， 将降低与细胞因子风暴相关的发病率和死亡率。 我们已经设计并合成了新型的小分子，它们是可溶性环氧化物水解酶的“双重”抑制剂 (sEH)和选择的次级抗炎靶点，包括环氧合酶-2（考克斯-2）。鉴于 这些目标参与炎症过程，我们相信我们的分子有潜力减轻 一项关键的创新将作为我们 一种策略是将两种抑制活性以 可以有效控制炎症过度而不需要全面的免疫抑制。我们的搭档 抑制剂PTUPB是由我们的科学顾问委员会主席， 布鲁斯吊床（加州大学戴维斯分校，加州）。 与COVID-19相关的ARDS和过度炎症。 sEH/考克斯-2双基因 抑制剂， 最近，PTUPB被证明是一种有效的抑制剂， 化疗诱导的细胞因子风暴。这项工作表明，与传统的反- 炎症药物，这种双重sEH/考克斯-2抑制剂可以防止细胞因子风暴，而无需伴随 可能由使用强效糖皮质激素如地塞米松引起免疫抑制。 我们假设我们的分子可以用于早期干预，而不是类固醇，以破坏 COVID-19疾病的进展并降低死亡率。 我们建议1）筛选50个我们的新分子 针对sEH和考克斯-2，并鉴定具有一系列针对靶向 酶，和2）在无偏高通量分析中筛选分子子集，以鉴定新的 具有预防或改善细胞因子风暴潜力的分子。