Catalysis and Inhibition of Gelatinases

明胶酶的催化和抑制

• 批准号: 7354759
• 负责人: D. K SRIVASTAVA
• 金额: $ 24.56万
• 依托单位: NORTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-16 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354759
• 关键词: Adverse effects; Area; Binding; Cancer cell line; Cancerous; Catalysis; Cell Line; Cleaved cell; Collagen Type IV; Effectiveness; Electronics; Encapsulated; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzyme Kinetics; Enzymes; Exhibits; Fatty Acids; Fibronectins; Gelatinase A; Gelatinases; Histidine; Ions; Isoenzymes; Knowledge; Lead; Ligands; Light; Lipids; Liposomes; Malignant Epithelial Cell; Matrix Metalloproteinases; Mediating; Molecular Conformation; Molecular and Cellular Biology; NMR Spectroscopy; Neoplasm Metastasis; Organic Chemistry; Outcome; Peptides; Pharmaceutical Preparations; Physiological; Prevention; Prevention strategy; Procedures; Recombinants; Research; Role; Site; Spectrum Analysis; Structure; Surface; System; Techniques; Thermodynamics; Tissues; Titrations; Transition Elements; Vesicle; Wound Healing; anticancer research; base; cancer therapy; design; inhibitor/antagonist; molecular modeling; prevent; research study; targeted delivery; tumor; tumor progression

The long term objective of the proposed research is to investigate the role of gelatinases in promoting invasion and metastasis in cancerous tissues, and its prevention by designing the mechanism based inhibitors as potential drugs. Besides their physiological roles in tissue remodeling, wound healing etc., gelatinase-A and -B are intimately involved in cancer progression and metastasis. Hence, the design of selective inhibitors against these enzymes as potential drugs, and their controlled delivery to the tumor sites are of significant importance in the area of the cancer research. During the proposed research, we will investigate the fundamental mechanism by which gelatinase-A and -B cleave their sequence specific (synthetic) triple-helical peptides (conjugated with fatty acids as well as incorporated in the lipid vesicles), synthesize the mechanism based inhibitors against these enzymes, and standardize the procedures for targeted delivery to selected cancer cell lines. The specific aims of the proposed research include the following: (1) Probe the selectivity and efficiency of gelatinase-A and -B in cleaving the sequence specific triple helical peptides and their fatty acid conjugates, (2) Design the structure based inhibitors for gelatinase- A and -B, and ascertain their potencies, (3) Develop strategy for delivering the inhibitors in selected carcinoma cell lines, and assess their effectiveness in preventing cellular invasions. These objectives will be accomplished by employing the techniques of synthetic organic chemistry, cellular and molecular biology, electronic spectroscopy, enzyme kinetics and thermodynamics, and molecular model building approaches. The outcome of the proposed research will lead to the prevention and/or treatment of cancers.

这项研究的长期目标是研究明胶酶在促进 癌组织中的侵袭和转移，以及通过设计基于 抑制剂作为潜在药物。除了它们在组织重塑、伤口愈合等方面的生理作用外， 明胶酶-A和明胶酶-B与癌症进展和转移密切相关。因此， 作为潜在药物的针对这些酶的选择性抑制剂，以及它们向肿瘤部位的受控递送 在癌症研究领域具有重要意义。在研究过程中，我们将 研究明胶酶-A和-B切割其序列特异性的基本机制 （合成的）三螺旋肽（与脂肪酸缀合以及掺入脂质囊泡中）， 合成针对这些酶的基于机制的抑制剂，并标准化程序， 靶向递送至选定的癌细胞系。拟议研究的具体目标包括： （1）探讨明胶酶-A和-B对序列特异性切割的选择性和效率 三螺旋肽及其脂肪酸缀合物，（2）设计基于结构的明胶酶抑制剂， A和-B，并确定其效力，（3）制定策略，以提供抑制剂在选定的 癌细胞系，并评估其在预防细胞侵袭中的有效性。这些目标将 采用合成有机化学、细胞和分子生物学技术完成， 电子光谱学、酶动力学和热力学以及分子模型构建方法。 拟议研究的结果将导致癌症的预防和/或治疗。