High Throughput Screen for Novel Anti-Rheumatic Compounds

新型抗风湿化合物的高通量筛选

• 批准号: 7999598
• 负责人: Dale J Christensen
• 金额: $ 33.33万
• 依托单位: COGNOSCI, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-06 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7999598
• 关键词: Affect; Age of Onset; Anti-Inflammatory Agents; Anti-inflammatory; Antirheumatic Agents; Apolipoprotein E; Arthritis; Autoimmune Diseases; Binding; Biological; Biological Assay; Cardiovascular Diseases; Cartilage; Cells; Cessation of life; Chronic; Clinical; Clinical Trials; Collagen Arthritis; Coupled; Data; Development; Disease; Disease Progression; Dose; Drug Compounding; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Fibroblasts; Fluorescence; Fluorescence Resonance Energy Transfer; Free Radicals; Funding; Goals; Grant; Human; Immune response; Immunocompetent; Immunoprecipitation; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Infiltrate; Injectable; Injection of therapeutic agent; Interleukin-1; Interleukin-12; Interleukin-6; Invaded; Joints; Lead; Libraries; Lung; Lymphocyte; MAPK14 gene; MAPK8 gene; Matrix Metalloproteinases; Mediating; Metalloproteases; Mitogen-Activated Protein Kinases; Modeling; Motion; Mus; Nature; Nitric Oxide; Oral; Osteoporosis; Outcome; Pain; Pathway interactions; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Phase; Phosphoric Monoester Hydrolases; Phosphorylation; Physiological; Population; Principal Investigator; Production; Property; Protein Dephosphorylation; Protein phosphatase; Proteins; Recruitment Activity; Rheumatoid Arthritis; Risk; Route; Series; Signaling Protein; Small Business Innovation Research Grant; Stimulus; Structure; Swelling; Symptoms; Synovial Cell; Synovial Membrane; Testing; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; Work; arthritis therapy; assay development; base; bone; collagenase 3; cytokine; economic cost; falls; functional disability; high throughput screening; human IRAK1 protein; improved; in vitro activity; in vivo; inhibitor/antagonist; inorganic phosphate; joint injury; mimetics; miniaturize; mitogen-activated protein kinase p38; monocyte; mouse model; neutralizing antibody; novel; pathogen; phase 2 study; pill; premature; prevent; protein phosphatase 2A inhibitor 2; public health relevance; research study; rheumatologist; small molecule; small molecule libraries; social; success

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines the joints. It is associated with increased risk of infection (pulmonary in particular), osteoporosis, and cardiovascular disease. Afflicting about 1 % of the population worldwide, RA causes pain, swelling, stiffness, and loss of motion in the joints, and, if unchecked, can cause irreversible joint damage, severe functional impairment, and premature death. Since RA thus far has no cure, most current therapies aim to slow disease progression and in recent years this has been accomplished with Disease Modifying Anti- Rheumatic Drugs (DMARD). While the anti-TNF1, anti-IL-12, and more recently anti-IL-6 DMARD compounds have successfully treated RA patients, a number of problems such as an injectable route of delivery and the development of neutralizing antibodies have lead to the search for small molecule compounds that can control RA symptoms when delivered as a daily pill. Cognosci has identified a novel series of anti-inflammatory apoE-mimetic peptides that suppress production of TNF1, IL-12, IL-6, and nitric oxide in vitro and in vivo, and thus have many of the properties necessary for an RA therapy. Using funds from a previous Phase I SBIR grant, we demonstrated that one of these peptides, COG133, inhibited production of cytokines and matrix metalloprotease (MMP) enzymes in primary human synovial fibroblasts. Furthermore, COG133 reduced disease symptoms and improved histological outcome in the murine collagen induced arthritis (CIA) model of RA. Recently, we have determined that COG133 acts by binding to and antagonizing the actions of the protein SET, also known as Inhibitor-2 of Protein Phosphatase 2A (I2PP2A). COG133's efficacy at reducing swelling, clinical scores, and cartilage damage in the paws of treated mice, coupled with COG133-mediated lowering of cytokine and MMP production from synovial cell fibroblasts, validates SET antagonism, and the associated PP2A activation, as a bona fide target for the development of novel RA therapeutics. We now propose to develop assays to enable high throughput screening to identify novel small molecule inhibitors of SET that will allow for development of an orally active anti-RA therapy that will inhibit multiple inflammatory pathways by antagonism of a single target. 1 PUBLIC HEALTH RELEVANCE: Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory autoimmune disease targeting the synovium, the tissue that lines the joints. It afflicts about 1 % of the population worldwide and causes pain, swelling, stiffness, and loss of motion in the joints, and, if unchecked, can cause irreversible joint damage, severe functional impairment, and premature death. Since RA thus far has no cure, most current therapies aim to slow disease progression and in recent years this has been accomplished with Disease Modifying Anti- Rheumatic Drugs (DMARD). While the anti-TNF1, anti-IL-12, and more recently anti-IL-6 DMARD compounds have successfully treated RA patients, a number of problems such as an injectable route of delivery and the development of neutralizing antibodies have lead to the search for small molecule compounds that can control RA symptoms when delivered as a daily pill. Cognosci has identified a novel series of anti-inflammatory peptides that suppress reduce disease symptoms and joint damage in an mouse model of RA. These data validate that a small compound that mimics the larger peptides could work as a daily therapy for RA that would be taken as a pill rather than injections. In this we propose to develop assays that will help to identify these novel drug leads that can be used to develop a new anti-RA therapy.

描述（由申请人提供）： 类风湿性关节炎 (RA) 是一种慢性、全身性炎症性自身免疫性疾病，以滑膜（关节内的组织）为靶点。它与感染（尤其是肺部感染）、骨质疏松症和心血管疾病的风险增加有关。 RA 困扰着全世界约 1% 的人口，它会导致关节疼痛、肿胀、僵硬和运动丧失，如果不加以控制，可能会导致不可逆的关节损伤、严重的功能障碍和过早死亡。由于 RA 迄今为止无法治愈，目前大多数疗法旨在减缓疾病进展，近年来，通过疾病修饰抗风湿药物 (DMARD) 实现了这一目标。虽然抗 TNF1、抗 IL-12 和最近的抗 IL-6 DMARD 化合物已成功治疗 RA 患者，但注射给药途径和中和抗体的开发等许多问题导致人们寻找小分子化合物，当每日服用药丸时可以控制 RA 症状。 Cognosci 已鉴定出一系列新型抗炎 apoE 模拟肽，可在体外和体内抑制 TNF1、IL-12、IL-6 和一氧化氮的产生，因此具有 RA 治疗所需的许多特性。利用之前第一阶段 SBIR 资助的资金，我们证明了其中一种肽 COG133 可以抑制原代人滑膜成纤维细胞中细胞因子和基质金属蛋白酶 (MMP) 的产生。此外，COG133 减轻了 RA 鼠胶原诱导关节炎 (CIA) 模型中的疾病症状并改善了组织学结果。最近，我们确定 COG133 通过与蛋白质 SET 结合并拮抗其作用来发挥作用，SET 也称为蛋白磷酸酶 2A (I2PP2A) 的抑制剂 2。 COG133 在减少治疗小鼠爪子肿胀、临床评分和软骨损伤方面的功效，加上 COG133 介导的滑膜细胞成纤维细胞细胞因子和 MMP 产生的降低，验证了 SET 拮抗作用和相关的 PP2A 激活，作为开发新型 RA 疗法的真正目标。我们现在建议开发检测方法，以实现高通量筛选，以确定新型 SET 小分子抑制剂，从而开发出口服活性抗 RA 疗法，通过拮抗单一靶点来抑制多种炎症途径。 1 公共卫生相关性： 类风湿性关节炎 (RA) 是一种慢性、全身性炎症性自身免疫性疾病，以滑膜（关节内的组织）为靶点。它困扰着全世界约 1% 的人口，导致关节疼痛、肿胀、僵硬和运动丧失，如果不加以控制，可能会导致不可逆的关节损伤、严重的功能障碍和过早死亡。由于 RA 迄今为止无法治愈，目前大多数疗法旨在减缓疾病进展，近年来，通过疾病修饰抗风湿药物 (DMARD) 实现了这一目标。虽然抗 TNF1、抗 IL-12 和最近的抗 IL-6 DMARD 化合物已成功治疗 RA 患者，但注射给药途径和中和抗体的开发等许多问题导致人们寻找小分子化合物，当每日服用药丸时可以控制 RA 症状。 Cognosci 已鉴定出一系列新型抗炎肽，可抑制 RA 小鼠模型的疾病症状和关节损伤。这些数据证实，模仿较大肽的小化合物可以作为 RA 的日常疗法，可以作为药丸而不是注射剂服用。在本文中，我们建议开发有助于识别这些可用于开发新的抗 RA 疗法的新药物先导物的测定方法。