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

项目总结 最近的研究表明，重症或危重冠状病毒病2019(新冠肺炎)患者 出现典型的败血症和感染性休克的临床表现，严重的医疗状况以 调节失调的全身炎症和促炎细胞因子的过度释放。细胞因子风暴是 随之而来的是免疫抑制，最终导致组织损伤、器官衰竭，甚至经常死亡。有效 脓毒症和感染性休克的治疗选择有限，死亡率极高，高达50% 对于脓毒症，高达80%用于感染性休克。双特异性磷酸酶3(DUSP3)，也称为痘苗病毒- H1相关磷酸酶(VHR)在单核细胞和巨噬细胞中高度表达，在 先天免疫反应的积极调节器。VHR基因缺失提供了强大的保护作用 内毒素休克和多菌感染性休克。VHR-/-小鼠对以下致炎性休克具有抵抗力 脂多糖(LPS)和盲肠结扎穿孔(CLP)诱导的脓毒症。此保护与 随着全身促炎症细胞因子如肿瘤坏死因子和白介素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 用于治疗败血症和感染性休克，这两种疾病导致了新冠肺炎的大部分死亡。 重要的是，VHR基因敲除小鼠是健康的、有生育能力的，并且没有表现出自发的表型异常， 提示针对VHR的特定药物可能没有有害的副作用。我们之前曾报道过 VHR小分子缓蚀剂MLS-0437605，具有良好的效力和选择性。我们建议对此进行优化 用于感染性休克CLP小鼠模型体内研究的化合物。生成特定VHR成功 在CLP模型中保护小鼠免受感染性休克的抑制剂将促进额外的临床前开发 在未来的研究中向临床候选人迈进。为了实现这些目标，我们的目标是1)定义变构 以MLS-0437605为靶点的VHR结合部位，以及2)优化效力、选择性和类药物 MLS-0437605的性质，并评估优化化合物在细胞和体内模型中的效果。 这项提议利用了一个成熟和运作良好的团队的专业知识，该团队一直在合作 在过去的几个磷酸酶药物发现项目中。

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.