Catalysis and Inhibition of Gelatinases

明胶酶的催化和抑制

• 批准号: 7033473
• 负责人: D. K SRIVASTAVA
• 金额: $ 24.54万
• 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/7033473
• 关键词: calorimetry; cancer prevention; carcinoma; cell line; chemical cleavage; chemical conjugate; chemical kinetics; chemoprevention; circular dichroism; collagenase; drug design /synthesis /production; enzyme mechanism; isozymes; liposomes; metastasis; molecular dynamics; molecular oncology; neoplasm /cancer invasiveness; nuclear magnetic resonance spectroscopy; peptide chemical synthesis; protein binding; synthetic peptide; thermodynamics; tissue inhibitor of metalloproteinases

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：拟议研究的长期目标是研究明胶酶在促进癌组织侵袭和转移中的作用，以及通过设计基于机制的抑制剂作为潜在药物来预防明胶酶。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，针对这些酶的选择性抑制剂的设计作为潜在的药物，并将其控制递送到肿瘤部位在癌症研究领域具有重要意义。在拟议的研究中，我们将研究明胶酶-A和-B切割其序列特异性（合成）三螺旋肽（与脂肪酸结合以及纳入脂质囊泡）的基本机制，合成基于机制的抑制剂对这些酶，并标准化的程序，有针对性地交付到选定的癌细胞系。拟议研究的具体目标包括：（1）探索明胶酶-A和-B在切割序列特异性三螺旋肽及其脂肪酸缀合物中的选择性和效率，（2）设计明胶酶- A和-B的基于结构的抑制剂，并确定它们的效力，（3）开发在选定的癌细胞系中递送抑制剂的策略，并评估它们在防止细胞入侵方面的有效性。这些目标将通过采用合成有机化学，细胞和分子生物学，电子光谱学，酶动力学和热力学，以及分子模型构建方法的技术来实现。拟议研究的结果将导致癌症的预防和/或治疗。