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.

项目摘要/摘要 世界卫生组织报告了超过2.16亿个确认的Covid-19及以上的病例 截至2021年8月31日，全球450万人死亡。 以前未受暴露（“幼稚”）人口导致大流行，对全球造成了悲惨的后果 规模。尽管流行病学数据表明，许多感染Covid-19的个体是无症状的 或解决他们的感染，大量的人会因失调和过多的细胞因子而严重患病 可能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 （或CRS）。这些结果表明，治疗高炎症以防止细胞因子风暴可以改善 COVID-19与严重病例相关的发病率和死亡率。在撰写本文时，治疗选择 由于单克隆抗体和remdesivir具有可疑的价值，地塞米松免疫抑制可能 在Covid-19患者中要有问题，可用的疫苗将受到生产，疫苗接种的限制 物流和公民的关注和怀疑主义（所谓的“疫苗犹豫”）。因此，我们推测该访问 到具有低副作用剖面的药物，能够有效控制细胞因子风暴 疾病的阶段，仍然是高未满足的医疗需求。我们打算用一种新颖的药物来填补这一空白 将减少与细胞因子风暴相关的发病率和死亡率。 我们设计和合成了可溶性环氧水解酶的“双重”抑制剂的新型小分子 （SEH）和选定的二级抗炎靶标，包括环氧酶-2（COX-2）。鉴于 这些靶标参与炎症过程，我们认为我们的分子有可能减轻 作为我们的一部分实施的关键创新 策略是将两种抑制活性纳入单个分子， 这可以有效地控制无全球免疫抑制的高炎症。我们的领先双重 抑制剂PTUPB被发现和特征是我们的科学顾问委员会的负责人，教授 布鲁斯·汉莫克（Bruce Hammock）（加利福尼亚加州大学戴维斯分校）。 ARDS和与Covid-19相关的高炎症。 双SEH/COX-2 抑制剂， 最近，PTUPB被证明是有效的抑制器 化学疗法诱导的细胞因子风暴。这项工作表明，与常规反 - 炎性药物，这种双SEH/COX-2抑制剂可以防止细胞因子风暴而无需随附 通过使用有效的糖皮质激素，例如地塞米松，可能导致的免疫抑制。 我们假设我们的分子可用于早期干预，而不是类固醇 199疾病的进展并降低死亡率。 我们建议1）屏幕50我们的新分子 针对SEH和COX-2，并确定具有一系列效力的分子的子集 酶和2）筛选该分子在公正的高通量分析中的子集以识别新型 具有预防或改善细胞因子风暴的潜力的分子。