Molecular Analyses of Folate and Antifolate Transport

叶酸和抗叶酸转运的分子分析

基本信息

批准号：
7947985
负责人：
Charles E. Dann
金额：
$ 27.6万
依托单位：
TRUSTEES OF INDIANA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7947985
关键词：
Address Advanced Development Adverse effects Affect Affinity Arthritis Binding Biological Assay Calorimetry Cell Cycle Kinetics Cell Line Cell surface Cells Chemotherapy-Oncologic Procedure Chronic Clinical Clinical Treatment Complex Cytotoxic agent Data Databases Development Discrimination Disease Dose Drug Delivery Systems Drug Design Epithelial Equilibrium Fluorescence Fluorescence Anisotropy Folate Folic Acid Folic Acid Antagonists Generations Glycosylphosphatidylinositols Hair Human Immunotherapy In Situ In Vitro Inflammatory Kinetics Knowledge Lead Ligand Binding Ligands Malignant Neoplasms Membrane Methotrexate Molecular Mutation Normal Cell Normal tissue morphology Patients Pharmaceutical Preparations Pharmacology Physiological Probability Protein Binding Psoriatic Arthritis Public Health Recording of previous events Research Research Personnel Roentgen Rays SLC19A1 gene Site Structural Models Structure Structure-Activity Relationship Surface Plasmon Resonance System Therapeutic Agents Thermodynamics Tissues Titrations Toxic effect Tumor Markers Work base cancer cell cancer therapy chemotherapy cytotoxic design folate-binding protein improved in vivo insight killings macrophage meetings mutant nanoparticle next generation novel overexpression preclinical study programs public health relevance receptor research study success three dimensional structure trafficking tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Folate-based drugs have been employed for decades in the treatment of cancer and inflammatory disease. These drugs, commonly termed antifolates, have met with success in clinical treatments but are severely limited due to their cytotoxic effects on normal cells. A prime example is the classic antifolate methotrexate (MTX), which is still commonly used at low doses in treatment of cancer, psoriasis and arthritic disease. Higher doses of MTX lead to obvious side effects including loss of hair as MTX preferentially kills rapidly dividing cells, normal or otherwise, without discrimination. Ideally, specific antifolates that target diseased cells without affecting normal cells could be developed. In studying folate transport, researchers have discovered that human folate receptor proteins (hFRs) are overexpressed in many tumor types and also activated macrophages at the site of inflammatory conditions (e.g. arthritis). Furthermore, the expression of hFRs on normal tissue is localized such that is not exposed to drugs administered intravenously. Taken together, antifolates that are designed to be taken up specifically by hFRs could be administered intravenously with minimal toxicity to normal tissue. Our proposal seeks to advance the development of novel hFR-specific antifolate drugs through extensive structural, thermodynamic, kinetic and cell-based characterizations of the interaction of hFRs with folate and antifolate ligands. Specifically our aims are to: 1) Determine the X-ray crystallographic structures of human membrane folate receptor types 1 and 2, targets for tissue selective delivery of experimental antifolate and folate-conjugate drugs, to aid in the design of new drugs to treat cancer and inflammatory diseases; 2) Elucidate the biophysical parameters of ligand binding and release by human folate receptors to ultimately delineate the desired structural features for folate-based drugs; and 3) Analyze human folate receptor mutants to identify key determinants of FRs required for trafficking and release of folates and antifolates in situ. Given the long history of folate-based drugs in disease treatment, the obvious lack of molecular insight into hFR-ligand interaction is disappointing at best. Completion of these studies will lead to a set of molecular parameters that will guide the rational design of the next generation of antifolates, leading to profound improvements in public health relating to cancer and chronic inflammatory disease. PUBLIC HEALTH RELEVANCE: Our proposed research program has the potential to improve public health by substantially improving the treatment of many prevalent human cancers. During chemotherapy treatment for cancer, many adverse side effects are realized by the patient due to the toxicity of the chemotherapeutic drugs in normal cells. Our work should lead to the development of novel drugs that specifically target cancer cells and therefore improve patient therapy with the added benefit of fewer side effects.

描述（由申请人提供）：基于叶酸的药物已用于治疗癌症和炎症性疾病。这些药物通常称为抗焦点，在临床治疗中取得了成功，但由于其细胞毒性对正常细胞的影响受到严重限制。一个主要的例子是经典的抗脱叶甲氨蝶呤（MTX），该甲氨蝶呤（MTX）仍然通常在低剂量的癌症，牛皮癣和关节炎治疗中使用。较高剂量的MTX导致明显的副作用，包括脱发，因为MTX优先杀死了迅速杀死正常或以其他方式的细胞，而无需歧视。理想情况下，可以开发出靶向患病细胞而不会影响正常细胞的特异性抗细胞。在研究叶酸传输时，研究人员发现，人类叶酸受体蛋白（HFRS）在许多肿瘤类型中过表达，并且在炎症性疾病部位（例如关节炎）也激活了巨噬细胞。此外，HFR在正常组织上的表达被定位，因此不会暴露于静脉内给药的药物。两者兼而有之，可以用最小的对正常组织的毒性静脉内给予专门摄取的抗染料。我们的建议旨在通过广泛的结构，热力学，动力学，动力学和基于细胞的基于细胞与叶酸和抗叶酸配体的相互作用的特征来推动新型HFR特异性抗脱外卵形药物的发展。具体而言，我们的目的是：1）确定人类膜叶酸受体类型1和2的X射线晶体学结构，用于组织选择性递送实验性抗卵酸和叶酸结合药物的靶标，以帮助设计新药以治疗癌症和炎症性疾病和炎症性疾病； 2）阐明人叶酸受体的配体结合和释放的生物物理参数，以最终描绘基于叶酸的药物所需的结构特征； 3）分析人类叶酸受体突变体，以确定运输和释放叶状和抗染料所需的FRS的关键决定因素。鉴于基于叶酸的药物在疾病治疗中的悠久历史，对HFR-s-conteraction的分子洞察力显然缺乏最充其量令人失望。这些研究的完成将导致一系列分子参数，这些参数将指导下一代抗染料的合理设计，从而导致与癌症和慢性炎性疾病有关的公共卫生的深刻改善。公共卫生相关性：我们提出的研究计划有可能通过大大改善许多普遍的人类癌症来改善公共卫生。在化学疗法治疗癌症期间，由于正常细胞中化学治疗药物的毒性，患者实现了许多不良副作用。我们的工作应导致新型药物的开发，这些药物专门针对癌细胞，因此可以改善患者疗法，并增加副作用的额外好处。