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: 8359633
• 负责人: TIMOTHY HUBIN
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8359633
• 关键词: Acquired Immunodeficiency Syndrome; Antibodies; Binding; Biological; Biomedical Research; CCR5 gene; CXCR4 Receptors; CXCR4 gene; Cells; Development; Disease; Flow Cytometry; Funding; Grant; HIV; Immune; Lead; Ligands; Macrocyclic Compounds; Malignant Neoplasms; Medicine; Methods; National Center for Research Resources; Neoplasm Metastasis; Oklahoma; Pharmaceutical Preparations; Play; Principal Investigator; Protease Inhibitor; RNA-Directed DNA Polymerase; Research; Research Infrastructure; Research Personnel; Resources; Rheumatoid Arthritis; Role; Route; Scheme; Screening procedure; Series; Source; Stem cell transplant; Stromal Cell-Derived Factor 1; Surface; System; Testing; Transition Elements; United States National Institutes of Health; chemokine; chemokine receptor; cost; 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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 项目摘要 CXCR4趋化因子受体位于免疫细胞表面，与特定的天然配体--基质细胞衍生因子-1(SDF-1)一起，已被发现在多种疾病状态中发挥作用。例如，CXCR4SDF-1系统参与了癌症的进展和转移，以及类风湿性关节炎的发展。此外，在过去的十年中，CXCR4和CCR5共同受体被发现是HIV进入细胞的途径，这引起了人们对通过进入抑制剂药物而不是目前偏爱逆转录酶和蛋白酶抑制剂进行治疗的新治疗方法的兴趣。我们的目标是开发CXCR4共受体的新拮抗剂。它们是构象固定的大环化合物及其过渡金属络合物。不受限制的大环类等价物是一种已知的CXCR4拮抗剂，已在临床上测试了其抗HIV有效性及其在促进干细胞移植方面的效用。我们提出的构象固定应该导致CXCR4结合的改善，以及阐明了过渡金属络合物与这个重要的趋化因子受体结合的结构要求。我们已经通过成功地为我们提出的两种构象固定产生了初始目标分子，从而证明了我们的合成方案的实用性。我们还使用流式细胞术方法对这些先导化合物进行了CXCR4结合筛选，以定量我们的拮抗剂对免疫细胞中过表达CXCR4受体的已知CXCR4结合抗体的抑制作用。我们现在请求支持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这一药物类别的基本设计特征。 相关性 趋化因子及其受体与多种疾病有关，包括艾滋病和癌症。我们打算生产专门针对CXCR4受体的分子，然后研究这些新分子如何有效地结合这个靶点。结果可能包括研究人员的新工具或新药本身。