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: 7725107
• 负责人: TIMOTHY HUBIN
• 金额: $ 11.26万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7725107
• 关键词: Antibodies; Binding; Biological; CXCR4 Receptors; CXCR4 gene; Cells; Class; Computer Retrieval of Information on Scientific Projects Database; Development; Disease; Flow Cytometry; Funding; Grant; HIV; Immune; Institution; Lead; Ligands; Macrocyclic Compounds; Methods; Neoplasm Metastasis; Numbers; Pharmaceutical Preparations; Play; Protease Inhibitor; Protein Overexpression; RNA-Directed DNA Polymerase; Research; Research Personnel; Resources; Rheumatoid Arthritis; Role; Route; Scheme; Screening procedure; Series; Source; Stem cell transplant; Surface; Testing; Transition Elements; United States National Institutes of Health; base; chemokine receptor; design; improved; inhibitor/antagonist; insight; interest; metal complex; novel therapeutics; preference; receptor; 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. CXCR4 chemokine receptors are found on the surface of immune cells, and together with their specific natural ligand, play a role in a number of disease states. CXCR4 has involvement in cancer progression and metastasis, and the development of rheumatoid arthritis. Within the last ten years the CXCR4 has been revealed as the entry route for some HIV strains 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 inhibitors for the CXCR4 co-receptor. They are rigid macrocyclic compounds and their transition metal complexes based on a known CXCR4 inhibitor that has been clinically tested for anti-HIV efficacy as well as its utility in facilitating stem cell transplantation. The rigidification we have implemented should lead to improved CXCR4 binding, as well as illuminating the structural requirements for binding transition metal complexes to this important 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 rigidification. These lead compounds have also been screened for CXCR4 binding using flow cytometry methods to quantify the inhibition of known CXCR4-binding antibodies by in immune cells which overexpress the CXCR4 receptor. We look forward to completing the synthesis and testing of a series of related compounds to gain further insights into the essential design features for this drug class through spectroscopic and biological studies.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 CXCR4 趋化因子受体存在于免疫细胞表面，与其特定的天然配体一起在多种疾病状态中发挥作用。 CXCR4 参与癌症进展和转移以及类风湿性关节炎的发展。 在过去十年中，CXCR4 已被揭示为某些 HIV 病毒株进入细胞的途径，这引起了人们对通过进入抑制剂药物进行治疗的新治疗方法的兴趣，而不是目前对逆转录酶和蛋白酶抑制剂的偏好。 我们的目标是开发 CXCR4 共受体的新抑制剂。 它们是刚性大环化合物及其基于已知 CXCR4 抑制剂的过渡金属络合物，该抑制剂已针对抗 HIV 功效及其促进干细胞移植的用途进行了临床测试。 我们实施的刚性化应该会改善 CXCR4 结合，并阐明过渡金属配合物与这一重要受体结合的结构要求。 我们已经通过成功生产我们提出的两种刚性化类型的初始目标分子，展示了我们的合成方案的实用性。 还使用流式细胞术方法筛选了这些先导化合物的 CXCR4 结合，以量化过度表达 CXCR4 受体的免疫细胞对已知 CXCR4 结合抗体的抑制。 我们期待完成一系列相关化合物的合成和测试，以通过光谱和生物学研究进一步了解此类药物的基本设计特征。