DEVELOPMENT AND SCREENING OF TRANSITION METAL COMPLEXES AS CXCR4 ANTAGONISTS

作为 CXCR4 拮抗剂的过渡金属配合物的开发和筛选

• 批准号: 8167532
• 负责人: TIMOTHY HUBIN
• 金额: $ 16.45万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8167532
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Binding; Biological; CCR5 gene; CXCR4 Receptors; CXCR4 gene; Cells; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Flow Cytometry; Funding; Grant; HIV; Immune; Institution; Lead; Ligands; Macrocyclic Compounds; Malignant Neoplasms; Medicine; Methods; Neoplasm Metastasis; Pharmaceutical Preparations; Play; Protease Inhibitor; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Route; Scheme; Screening procedure; Series; Source; Stem cell transplant; Stromal Cells; Surface; System; Testing; Transition Elements; United States National Institutes of Health; chemokine; chemokine receptor; design; improved; inhibitor/antagonist; insight; interest; metal complex; novel therapeutic intervention; overexpression; preference; receptor; tool; tumor progression

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Project Summary CXCR4 chemokine receptors are found on the surface of immune cells, and together with the specific natural ligand, stromal cell-derived factor-1¿ (SDF-1¿), have been revealed to play a role in a number of disease states. For example, the CXCR4SDF-1¿ system has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Also, within the last ten years the CXCR4 and CCR5 co-receptors have been revealed as the entry route for HIV into cells, generating interest in a new therapeutic approach to treatment via entry inhibitor drugs rather than the current preference for reverse transcriptase and protease inhibitors. Our aim is to develop new antagonists for the CXCR4 co-receptor. They are conformationally fixed macrocyclic compounds and their transition metal complexes. The unrestrained macrocyclic equivalent is a known CXCR4 antagonist that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The conformational fixing we propose should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important chemokine receptor. We have already demonstrated the utility of our synthetic schemes by successfully producing the initial target molecules for both of our proposed types of conformational fixing. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by our antagonists in immune cells which overexpress the CXCR4 receptor. We now request support to complete the synthesis and testing of a series of compounds, and gain further insights into the essential design features for this drug class through spectroscopic and biological studies. Relevance Chemokines and their receptors are involved in multiple diseases, including AIDS and cancer. We intend to produce molecules that will specifically target the CXCR4 receptor, and then study how efficiently these new molecules bind this target. Results may include new tools for researchers or new medicines themselves.

该副本是使用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这是调查员的机构。 项目摘要 CXCR4趋化因子受体在免疫细胞的表面上发现，并与特定的天然配体，基质细胞衍生的因子-1（SDF-1？）一起在许多疾病状态中发挥了作用。例如，CXCR4 SDF-1系统参与了癌症进展和转移，以及类风湿关节炎的发展。同样，在过去的十年中，CXCR4和CCR5共受体已被揭示为HIV进入细胞的进入途径，引起人们对通过进入抑制剂药物进行新的治疗方法的兴趣，而不是当前对逆转录酶和蛋白酶抑制剂的偏爱。我们的目的是为CXCR4共受体开发新的拮抗剂。它们是构象固定的大环化合物及其过渡金属复合物。不受约束的大环效物是已知的CXCR4拮抗剂，已在临床上测试了抗HIV效率以及其在支持干细胞移植方面的效用。我们建议的构象固定应导致CXCR4结合的改善，并阐明结合过渡金属复合物与该重要趋化因子受体的结构要求。已经通过成功地生产了我们提出的两种宪法固定类型的初始靶标分子来证明我们的合成方案的实用性。这些铅化合物还使用流式细胞仪方法筛选了CXCR4结合，以量化我们的拮抗剂在过表达CXCR4受体的免疫细胞中抑制已知的CXCR4结合抗体。现在，我们请求支持以完成一系列化合物的合成和测试，并通过光谱和生物学研究进一步了解该药物类别的基本设计特征。 关联 趋化因子及其受体参与多种疾病，包括艾滋病和癌症。我们打算产生将专门针对CXCR4受体的分子，然后研究这些新分子如何结合该靶标。结果可能包括针对研究人员或新药物本身的新工具。