Development of the New Synthetic Triterpenoid CDDO-2P-Im for Chemoprevention of the ARDS of COVID-19

项目摘要 新冠肺炎感染与临床合并症患者的大量死亡有关，包括 吸烟、高龄和糖尿病。在这些患者中，新冠肺炎感染会导致 高炎症状态导致血管渗漏、间质水肿、透明膜形成和ARDS。 需要ICU的新冠肺炎患者循环中IL-6、GM-CSF、MCP和MIP1(CCL2)水平较高 与那些患有简单疾病的人相比，细胞因子的水平更高。这种高炎症综合征(又名“细胞因子” 风暴“)是ARDS和多器官衰竭的前驱症状。慢性支气管炎患者的支气管肺泡液(BALF) 重症新冠肺炎富含CCL2，CCL2是推动单核细胞募集的最强大的趋化因子之一 进入肺部。值得注意的是，细胞因子风暴也与SARS冠状病毒和MERS的广泛肺损伤有关。 冠状病毒感染，表明呼吸道人畜共患病普遍存在先天高炎症。没有 目前可用的有效治疗方法，可部署为干预措施以预防或改善 新冠肺炎的细胞因子风暴。为了满足这一需求，我们的研究团队正在积极参与临床前研究 一种优化的先导剂(CDDO-2P-Im，或‘2P-Im’)的开发，这是一种高效的合成三萜类化合物，它是 在一类被公认为有效的宿主炎症调节剂的小分子中最先进的 回应。我们的数据显示，2P-Im广泛地抑制了细胞因子网络和相关途径的表达 过度发炎。尤其是2P-Im及其相关衍生物是巨噬细胞的有效抑制物 激活，在皮摩尔浓度下抑制人巨噬细胞产生MIP1(CCL2)。2P- IM是一种创新的新药，其作用机制是目前任何其他药物所不具备的 调查研究在治疗新冠肺炎中的应用。我们设想2P-IM将作为口服药物提供给患者 部署用于预防巨噬细胞激活综合征和阻止进展为新冠肺炎急性呼吸窘迫综合征 高危人群中的疾病。2P-IM也有可能在门诊环境中用作化学预防 减少急救人员、居住在集体环境中的居民和其他暴露在高危人群中的风险的养生法 敬新冠肺炎。初步数据显示在流感疗效检测中具有强大的细胞保护作用 甲型H1N1病毒和甲型H3N1流感病毒。通过三萜类治疗公司(TTX)和 德克萨斯生物医学研究所，我们将在已建立的 新冠肺炎的小鼠模型。具体地说，我们将定义2P-IM预防细胞病变效应的能力 在建立、验证的新冠肺炎体外模型(AIM 1)中感染SARS-CoV-2；并在体内验证 2P-Im对SARS-CoV-2诱导的炎症的疗效及对已建立的患者的促进生存能力 K18-hACE2新冠肺炎小鼠模型(目的2)。拟议的计划将导致IND的批准，这将允许 2P-IM在新冠肺炎患者中的未来临床试验，这是本项目的最终目标。

PROJECT ABSTRACT COVID-19 infection is associated with substantial mortality in patients with clinical co-morbidities, including smoking, advanced age and diabetes mellitus. In these patients, COVID-19 infection leads to a hyperinflammatory state producing vascular leak, interstitial edema, hyaline membrane formation and ARDS. COVID-19 patients requiring ICU admission have high circulating levels of IL-6, GM-CSF, MCP and MIP1 (CCL2) cytokines compared to those with uncomplicated illnesses. This hyper-inflammation syndrome, (aka “cytokine storm”) is a prodromal feature of ARDS and multi-organ failure. Bronchoalveolar fluids (BALF) from patients with severe COVID-19 are enriched in CCL2, one of the most potent chemokines driving the recruitment of monocytes into the lung. Of note, cytokine storm is also associated with extensive lung damage in SARS-CoV and MERS- CoV infections, suggesting that innate hyper-inflammation is common to respiratory zoonoses. There is no effective treatment currently available that may be deployed as an intervention to either prevent or ameliorate the cytokine storm of COVID-19. To address this need, our research team is actively engaged in the preclinical development of an optimized lead agent (CDDO-2P-Im, or ‘2P-Im’), a highly potent synthetic triterpenoid that is the most advanced among a class of small molecules recognized as effective modifiers of the host inflammatory response. Our data show that 2P-Im broadly inhibits expression of cytokine networks and pathways underlying hyper-inflammation. In particular, 2P-Im and its related derivatives are potent suppressors of macrophage activation, suppressing the production of MIP1 (CCL2) by human macrophages at picomolar concentrations. 2P- Im is an innovative new drug, with a mechanism of action not shared by any other drug currently under investigation for in use in treating COVID-19. We envision 2P-Im will be provided to patients as an oral agent deployed to prevent macrophage activation syndrome and disrupt progression to the ARDS of COVID-19 disease in high-risk populations. 2P-Im also has potential for use in the outpatient setting as a chemopreventive regimen to reduce risk in first responders, residents living in group settings, and other high-risk groups exposed to COVID-19. Preliminary data demonstrate potent cytoprotective effects in assays of efficacy against Influenza virus A H1N1 and Influenza virus A H3N2. Through partnership between Triterpenoid Therapeutics (TTX) and the Texas Biomedical Research Institute, we will pursue full-scale, IND-enabling efficacy studies in established mouse models of COVID-19. Specifically, we will define the capacity of 2P-Im to prevent the cytopathic effects of SARS-CoV-2 in established, validated in vitro models of COVID-19 (Aim 1); and demonstrate the in vivo efficacy of 2P-Im against SARS-CoV-2 induced inflammation and capacity to promote survival in the established K18-hACE2 mouse model of COVID-19 (Aim 2). The proposed plan will lead to approval of an IND that will allow for future clinical trials of 2P-Im in patients with COVID-19, which is the ultimate goal of this project.