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

靶向 VHR 磷酸酶治疗 COVID-19 患者脓毒症

• 批准号: 10385773
• 负责人: Lutz Tautz
• 金额: $ 24.38万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-06 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10385773
• 关键词: Allosteric Site; Amino Acids; B-Lymphocytes; Binding; Binding Sites; Biological Assay; Biophysics; COVID-19; COVID-19 mortality; COVID-19 patient; Caring; Catalytic Domain; Cells; Cessation of life; Clinical; Consensus; Coronavirus Infections; Critical Illness; Cysteine; Data; Drug Kinetics; Drug Targeting; Dual Specificity Phosphatase 3; Endotoxins; Enzymes; Future; Genetic; Hospitals; Immunosuppression; Infection; Inflammatory; Innate Immune Response; Interleukin-6; International; Knockout Mice; Knowledge; Lead; Lipopolysaccharides; Medical; Modeling; Mus; NMR Spectroscopy; Organ failure; Patients; Pharmaceutical Preparations; Phenotype; Phosphoric Monoester Hydrolases; Platelet Count measurement; Play; Production; Property; Protein Tyrosine Phosphatase; Reporting; Resistance; Role; Sepsis; Septic Shock; Shock; Specificity; Structure; Symptoms; T-Lymphocyte; TNF gene; Testing; Tissues; Vaccinia; analog; base; cecal ligation puncture; clinical candidate; cytokine; cytokine release syndrome; drug discovery; drug metabolism; effective therapy; experimental study; improved; in vivo; in vivo Model; inhibitor; macrophage; monocyte; mortality; mouse model; neutrophil; novel; novel therapeutic intervention; phosphatase inhibitor; preclinical development; response; side effect; small molecule inhibitor; success; systemic inflammatory response; targeted treatment

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.

项目概要 最近的研究表明，重症或危重症 2019 冠状病毒病（COVID-19）患者 出现败血症和败血性休克的典型临床表现，严重的医疗状况的特点是 全身炎症失调和促炎细胞因子过度释放。细胞因子风暴是 其次是免疫抑制，最终导致组织损伤、器官衰竭，甚至死亡。有效的 败血症和败血性休克的治疗选择有限，死亡率极高，高达 50% 用于败血症，高达 80% 用于败血性休克。双特异性磷酸酶 3 (DUSP3)，也称为牛痘- H1 相关磷酸酶 (VHR) 在单核细胞和巨噬细胞中高表达，在 先天免疫反应的正调节剂。 VHR 基因删除可提供强有力的保护 内毒素休克和多种微生物感染性休克。 VHR-/-小鼠对由以下因素引起的炎症休克具有抵抗力 脂多糖（LPS）和盲肠结扎穿刺（CLP）诱导的败血症。此保护关联 促炎性细胞因子（如 TNF 和 IL-6）的全身产生减少，这些细胞因子在 COVID-19 患者。基于这些发现，用小分子抑制剂抑制 VHR 可能是有益的 用于治疗败血症和败血性休克，这两种疾病是导致大多数 COVID-19 死亡的原因。 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， 这表明针对 VHR 的特定药物可能没有有害的副作用。我们之前报道过一个 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。成功生成特定VHR 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 成为未来研究中的临床候选人。为了实现这些目标，我们的目标是 1) 定义变构 MLS-0437605 靶向的 VHR 中的结合位点，以及 2) 优化效力、选择性和类药性 MLS-0437605 的特性，并评估优化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，该团队一直在合作 过去参与过多个磷酸酶药物发现项目。