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

项目摘要 COVID-19感染与临床合并症患者的大量死亡相关，包括 吸烟、高龄和糖尿病。在这些患者中，COVID-19感染导致 高炎症状态，导致血管渗漏、间质水肿、透明膜形成和ARDS。 需要入住ICU的COVID-19患者的IL-6、GM-CSF、MCP和MIP 1（CCL2）循环水平较高 细胞因子与那些没有复杂疾病的人相比。这种过度炎症综合征（又称"细胞因子 风暴"）是ARDS和多器官衰竭的前驱特征。支气管肺泡液（BALF）， 严重的COVID-19富含CCL2，这是驱动单核细胞募集的最有效的趋化因子之一 进入肺部值得注意的是，细胞因子风暴也与SARS-CoV和MERS的广泛肺损伤有关。 CoV感染，表明先天性过度炎症是呼吸道人畜共患病的常见现象。没有 目前可用的有效治疗方法，可以作为干预措施， 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开展临床前研究。 开发了一种优化的先导剂（CDDO-2P-Im或"2P-Im"），这是一种高效的合成三萜类化合物， 在一类被认为是宿主炎症的有效调节剂的小分子中， 反应我们的数据表明，2P-Im广泛抑制细胞因子网络和潜在途径的表达， 过度炎症特别地，2P-Im及其相关衍生物是巨噬细胞增殖的有效抑制剂。 活化，抑制人巨噬细胞在皮摩尔浓度下产生MIP 1（CCL 2）。2P- IM是一种创新的新药，其作用机制与目前正在研究的任何其他药物都不相同。 用于治疗COVID-19的研究。我们设想2P-Im将作为口服药物提供给患者 用于预防巨噬细胞活化综合征并阻止COVID-19的ARDS进展 高危人群的疾病。2P-Im也有可能在门诊环境中用作化学预防剂， 降低第一反应者、居住在群体环境中的居民和其他高危人群暴露风险的方案 新冠肺炎初步数据表明，在抗流感病毒的有效性试验中具有强效细胞保护作用 甲型流感病毒H1N1和甲型流感病毒H3N2。通过三萜类化合物治疗（TTX）和 德州生物医学研究所，我们将追求全面的，IND使有效性研究，在建立 COVID-19的小鼠模型。具体而言，我们将定义2P-Im防止细胞病变效应的能力 SARS-CoV-2在COVID-19体外模型中的作用（目的1）;并证明体内 2P-Im对SARS-CoV-2诱导的炎症的有效性和促进建立的 COVID-19的K18-hACE2小鼠模型（目的2）。拟议的计划将导致IND的批准， 用于2P-Im在COVID-19患者中的未来临床试验，这是该项目的最终目标。

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.