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

项目摘要/摘要 世界卫生组织报告了超过2.16亿例新冠肺炎感染和更多确诊病例 截至2021年8月31日，全球有450万人死亡。这种新的冠状病毒迅速进入一个 以前未接触过的(天真的)人群导致了一场大流行，对全球 比例。尽管流行病学数据表明，许多感染新冠肺炎的人没有症状 或解决他们的感染，相当多的人患上了严重的疾病，细胞因子失调和过多 产生可导致一种称为细胞因子风暴(CS)或细胞因子释放综合征的病理情况 (或CRS)。这些结果表明，预防细胞因子风暴的过度炎症治疗可能会有所改善 重症患者新冠肺炎相关发病率和死亡率。在撰写本文时，治疗方案包括 由于单抗和瑞希韦的价值值得怀疑，地塞米松免疫抑制可能 新冠肺炎患者出现问题，可用的疫苗(S)将受到生产、接种的限制 后勤和公民的关切和怀疑(所谓的“疫苗迟疑”)。因此，我们推测访问 一种副作用较低的药物，能够有效地控制细胞因子风暴，而不管 疾病阶段，仍然是一个高度未得到满足的医疗需求。我们打算用一类新的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。 我们设计并合成了一种新型的小分子，它们是可溶性环氧化物水解酶的‘双重’抑制剂。 (SEH)和选定的二级抗炎靶点，包括环氧合酶-2(COX-2)。给定 这些靶点参与炎症过程，我们相信我们的分子有潜力减轻 一项关键创新将作为我们的 策略是将这两种抑制活性合并到单个分子中，形式为 这可以有效地控制过度炎症，而不需要全球免疫抑制。我们的领头羊双打 抑制剂PTUPB被发现，并由我们的科学顾问委员会主席，教授 布鲁斯·哈莫克(加州大学戴维斯分校)。 与新冠肺炎相关的不良反应和炎症反应。 双重sEH/COX-2 抑制剂， 最近，PTUPB被证明是一种有效的血管生成抑制因子。 化疗引发的细胞因子风暴。这项工作表明，与传统的反 炎性药物，这种双重的sEH/COX-2抑制剂可以预防细胞因子风暴而不伴随 免疫抑制可能是由于使用强效糖皮质激素如地塞米松引起的。 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 减少新冠肺炎疾病的进展，降低死亡率。 我们建议筛选出50个我们的新型分子 抗sEH和COX-2，并鉴定具有一定效力范围的分子子集 酶，以及2)在无偏高通量分析中筛选分子子集以识别新的 有可能阻止或改善细胞因子风暴的分子。

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.