Targeting the VHR phosphatase for the treatment of sepsis in COVID-19 patients

项目摘要 最近的研究表明，2019冠状病毒病（COVID-19）重症或危重患者 出现脓毒症和脓毒性休克的典型临床表现，严重的医学状况，特征为 失调的全身性炎症和促炎细胞因子的过度释放。细胞因子风暴是 随后是免疫抑制，最终导致组织损伤、器官衰竭，并常常导致死亡。有效 脓毒症和脓毒性休克的治疗选择有限，死亡率极高，高达50%。 脓毒症和脓毒性休克的发病率高达80%。双特异性磷酸酶3（DUSP 3），也称为牛痘- H1相关磷酸酶（VHR）在单核细胞和巨噬细胞中高度表达，并在以下方面发挥关键作用： 先天免疫反应的正调节器VHR的基因缺失赋予了针对以下疾病的强有力的保护： 内毒素休克和多微生物感染性休克。VHR-/-小鼠对由以下物质诱导的炎性休克具有抗性： 脂多糖（LPS）和盲肠结扎穿孔（CLP）诱导的脓毒症。这种保护与 全身性促炎细胞因子如TNF和IL-6的产生减少，这些细胞因子在 新冠肺炎患者。基于这些发现，用小分子抑制剂抑制VHR可能是有益的 用于治疗脓毒症和脓毒性休克，这是导致大多数COVID-19死亡的原因。 重要的是，VHR敲除小鼠是健康的、可生育的，并且没有显示出自发的表型异常， 这表明靶向VHR的特异性药物可能没有有害的副作用。我们之前报道了一个 VHR小分子抑制剂，MLS-0437605，具有良好的效力和选择性。我们建议优化这一点 化合物用于感染性休克的CLP小鼠模型中的体内研究。成功生成特定VHR 在CLP模型中保护小鼠免于感染性休克的抑制剂将促进额外的临床前开发 在未来的研究中成为临床候选人。为了实现这些目标，我们的目标是1）定义变构 MLS-0437605靶向VHR中的结合位点，和2）优化效价、选择性和药物样 MLS-0437605的性质，并评估优化的化合物在细胞和体内模型中的功效。 该提案利用了一个已建立且运作良好的团队的专业知识， 参与过几个磷酸酶药物研发项目

PROJECT SUMMARY Recent studies have demonstrated that severe or critically ill coronavirus disease 2019 (COVID-19) patients develop typical clinical manifestations of sepsis and septic shock, serious medical condition characterized by dysregulated systemic inflammation and excessive release of proinflammatory cytokines. The cytokine storm is followed by immunosuppression, ultimately leading to tissue damage, organ failure, and often death. Effective treatment options for sepsis and septic shock are limited, and the mortality rate is extremely high with up to 50% for sepsis and up to 80% for septic shock. The dual-specificity phosphatase 3 (DUSP3), also known as Vaccinia- H1-related phosphatase (VHR), is highly expressed in monocytes and macrophages and plays a critical role as a positive regulator of the innate immune response. Genetic deletion of VHR confers strong protection against endotoxin shock and polymicrobial septic shock. VHR-/- mice are resistant to inflammatory shock induced by lipopolysaccharides (LPS) and cecum ligation and puncture (CLP)-induced sepsis. This protection is associated with decreased systemic production of proinflammatory cytokines such as TNF and IL-6, which are elevated in COVID-19 patients. Based on these findings, inhibition of VHR with small molecule inhibitors may be beneficial for the treatment of sepsis and septic shock, which are responsible for the majority of COVID-19 deaths. Importantly, VHR knockout mice are healthy, fertile, and show no spontaneous phenotypic abnormalities, suggesting that specific drugs targeting VHR may have no deleterious side effects. We previously reported a VHR small molecule inhibitor, MLS-0437605, with good potency and selectivity. We propose to optimize this compound for in vivo studies in the CLP mouse model of septic shock. Success in generating a specific VHR inhibitor that protects mice from septic shock in the CLP model will prompt additional preclinical development towards a clinical candidate in future studies. To achieve these objectives, our aims are to 1) define the allosteric binding site in VHR targeted by MLS-0437605, and 2) to optimize the potency, selectivity, and drug-like properties of MLS-0437605, and to assess the efficacy of optimized compounds in cellular and in vivo models. This proposal leverages the expertise of an established and well-functioning team that has been collaborating on several phosphatase drug discovery projects in the past.