Therapeutic Application of Small Molecule MIF Inhibitors in Rheumatoid Arthritis

小分子MIF抑制剂在类风湿性关节炎中的治疗应用

基本信息

批准号：
8604375
负责人：
Thomas Yoonsang Cho
金额：
$ 12.41万
依托单位：
SAINT LOUIS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-01-15 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8604375
关键词：
Active Sites Address Affect Anti-Inflammatory Agents Antiinflammatory Effect Atherosclerosis Autoimmune Diseases Binding Binding Sites Biological Assay CD44 gene CXCR4 gene Catalytic Domain Cell Adhesion Molecules Cell Line Cells Chemistry Chemotaxis Collaborations Collagen Arthritis Computer Simulation Cytokine Receptors Data Disease Disease model Drug Design Drug Kinetics Fibroblasts Figs - dietary G-Protein-Coupled Receptors Glomerulonephritis IL8RB gene Immune In Vitro Inflammation Inflammatory Kinetics Knock-out Link Lupus Measures Mediating Migration Inhibitory Factor Modeling Molecular Models Mus Mutation Organ Outcome Parents Patients Pharmaceutical Preparations Phosphotransferases Pilot Projects Play Process Property Receptor Activation Receptor Protein-Tyrosine Kinases Recruitment Activity Reporting Research Resolution Rheumatoid Arthritis Role Septic Shock Serum Severities Signal Pathway Signal Transduction Signaling Protein Solvents Specificity Structure Structure-Activity Relationship Symptoms Synovial Fluid Systemic Lupus Erythematosus Testing Therapeutic Therapeutic Effect Time Vertebral column X ray diffraction analysis X-Ray Crystallography X-Ray Diffraction abstracting analog base cytokine functional group improved indexing inhibitor/antagonist innovative technologies invariant chain molecular modeling monocyte novel pharmacophore phenylpyruvate tautomerase receptor receptor binding small molecule small molecule libraries therapeutic target three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Abstract Macrophage migration inhibitory factor (MIF) plays an important role for the recruitment of innate and adaptive immune cells to the place of inflammation. MIF also activates various intracellular signaling pathways in the recruited cells for the release of other cytokines and the expression of cell adhesion molecules. The unique feature as a cytokine, MIF has catalytic (tautomerase) activity, which is yet controversial for its link to the immunological activity of MIF. Despite this controversy, recent studies support that the residues around the active site, not in the active site, play a role in interacting with the receptors. To date, three MIF receptors have been reported: 1) an invariant chain CD74, and CXC cytokine receptors 2) CXCR2 and 3) CXCR4. CD74 does not have tyrosine receptor kinase like signaling domain and requires CD44 that contains a kinase domain. It seems that all these receptors except CD44 directly interact with MIF. These receptors are also known to form hetero-oligomers. Our recent catalytic and chemotactic assays demonstrated that strong competitive inhibitors were not always more potent to the MIF-mediated chemotaxis than weak non-competitive inhibitors. In addition, crystal structures of MIIF inhibitors reveal that free functional groups are exposed to the solvent and available for the interference with receptor binding. In an effort to 1) investigate the interplay between MIF and its receptors and 2) to develop MIF inhibitors as antiinflammatory therapeutics, we identified a structurally diverse set of small molecule inhibitors, performed kinetic and structural characterization. The identified inhibitors will be optimized as drug leads in collaboration with Dr. William Jorgensen (Yale Chemistry Department). Furthermore, ones with good pharmacological properties in vitro will be subject to pharmacokinetics and tested for therapeutic effect in a murine model of rheumatoid arthritis. Outcomes of this proposed research will allow us to better understand MIF action to its receptors and also will provide potential drug leads for the treatment of inflammatory diseases.

描述（由申请人提供）：摘要巨噬细胞迁移抑制因子（MIF）对于将先天性和适应性免疫细胞募集到炎症部位起着重要作用。 MIF 还激活招募的细胞中的各种细胞内信号传导途径，以释放其他细胞因子和表达细胞粘附分子。作为细胞因子，MIF 具有催化（互变异构酶）活性，但其与 MIF 免疫活性的联系仍存在争议。尽管存在争议，但最近的研究支持活性位点周围的残基，而不是活性位点内的残基，在与受体相互作用中发挥作用。迄今为止，已报道了三种 MIF 受体：1) 不变链 CD74 和 CXC 细胞因子受体 2) CXCR2 和 3) CXCR4。 CD74 不具有酪氨酸受体激酶样信号结构域，需要包含激酶结构域的 CD44。似乎除 CD44 之外的所有这些受体都直接与 MIF 相互作用。还已知这些受体形成异源寡聚物。我们最近的催化和趋化测定表明，强竞争性抑制剂并不总是比弱非竞争性抑制剂对 MIF 介导的趋化作用更有效。此外，MIIF 抑制剂的晶体结构表明，游离官能团暴露于溶剂中，可干扰受体结合。为了 1) 研究 MIF 及其受体之间的相互作用，以及 2) 开发 MIF 抑制剂作为抗炎治疗药物，我们鉴定了一组结构多样的小分子抑制剂，并进行了动力学和结构表征。已确定的抑制剂将与 William Jorgensen 博士（耶鲁大学化学系）合作优化作为先导药物。此外，在体外具有良好药理特性的药物将接受药代动力学研究，并在类风湿性关节炎小鼠模型中测试治疗效果。这项拟议研究的结果将使我们能够更好地了解 MIF 对其受体的作用，并为治疗炎症性疾病提供潜在的药物先导化合物。