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Synthesis of New Ligands for the Characterization of Siderophore-ExFABP Interacti

用于表征铁载体-ExFABP相互作用的新配体的合成

基本信息

批准号：
7422080
负责人：
Juan R Del Valle
金额：
$ 9.5万
依托单位：
NEW MEXICO STATE UNIVERSITY LAS CRUCES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7422080
关键词：
Affect Affinity Anti-Bacterial Agents Antibiotic Therapy Antibiotics Apoptosis Bacteria Bacterial Infections Bacterial Proteins Binding Binding Proteins Biological Assay Cancer Patient Chelating Agents Chemicals Chickens Class Complement Complex Crystallization Crystallography Drops Effectiveness Embryonic Development Enteral Enterobactin Exhibits Family Fluorescence Foundations Goals Growth Health Human Immune system In Vitro Infection Investigation Iron Lactoferrin Ligand Binding Ligands Malignant Neoplasms Methodology Microbe Mus Mutation Neutropenia Numbers Nutrient Patients Peptides Play Population Heterogeneity Preparation Proline Protein Analysis Protein Binding Proteins Pseudomonas Pseudomonas aeruginosa Range Research Resistance Risk Role Sampling Series Siderophores Source Specificity Sulfur Therapeutic Variant Water abstracting analog antimicrobial base cancer therapy carbene chemical synthesis design in vivo member microbial mycobacterial neutrophil novel novel strategies pathogen phenolate pyochelin pyoverdin response small molecule structural biology tumor growth tumorigenesis

项目摘要

ABSTRACT Cancer and cancer therapy are commonly accompanied by a severe weakening of the immune system. Bacteria are responsible for the majority of adventitious infections in neutropenic cancer patients and thus pose a significant health risk. Preliminary studies have shown that human siderocalin, a member of the lipocalin family of binding proteins, binds to microbial ferric siderophores and inhibits bacetrial growth through the sequestration of iron. Given that mamalian iron levels drop in response to pathogens and tumor growth, targeted binding of iron via ferric microbial siderophore complexes may be a useful strategy in the treatment of cancer and bacterial infections. We have found that Ex-FABP, a related lipocalin protein expessed during chicken embryo development, also binds ferric siderophore complexes of distinct structural classes. Our aim is to chemically synthesize naturally occurring and designed analogs of bacterial siderophores in order to achieve a complete understanding of siderophore-specific innate immune system interactions. In an effort to parse the recognition modes of siderocalin and Ex-FABP, we will prepare oxo and methylene variants of pyochelin, a Pseudomonas siderophore that binds to Ex-FABP, but not to siderochelin. The specific hypothesis is that the sulfur atom in the thiozoline ring of pyochelin preculdes binding to siderocalin due to a steric clash with a tightly bound water molecule in the calyx. Replacement of a thiazoline with an oxazoline ring will potentially mimic the binding mode of other high-affinity siderocalins such as the carboxymycobactins. Because naturally occuring pyochelin also exists as an unstable mixture of diastereomers, we propose to synthesize configurationally stable proline-based analogs in order to determine the discrete stereochemical requirements of Ex-FABP binding. We will also undertake the first chemical synthesis of (group I) pyoverdin, a complex peptide that binds specifically to Ex-FABP. The advantages of total chemical synthesis include the ability to pursue synthetic analogs and the isolation of homogenous ligand that is difficult to obtain from bacterial sources. Once synthetically pure samples of these sideophores are available, we will proceed with quanitative binding studies, in vitro growth arrest assays, and x-ray crystallography. Results emanating from this research will aid in the identification of other protein-specific microbial siderophores and lay the foundation for protein mutation as a means toward microbe-selective antibiotic therapy.

摘要