Catalysis and Inhibition of Gelatinases

这项拟议研究的长期目标是调查明胶酶在促进 癌组织的侵袭转移及其机制设计的预防 作为潜在药物的抑制剂。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与癌症的进展和转移密切相关。因此，设计的 作为潜在药物的针对这些酶的选择性抑制剂及其对肿瘤部位的控制递送 在癌症研究领域具有重要意义。在拟议的研究期间，我们将 研究明胶酶-A和明胶酶-B切割其序列特异性的基本机制 (合成)三螺旋多肽(与脂肪酸结合并结合在脂泡中)， 合成针对这些酶的基于机理的抑制剂，并标准化程序 靶向递送到选定的癌细胞系。拟议研究的具体目标包括 (1)探讨明胶酶-A和明胶酶-B切割序列特异性的选择性和效率 三螺旋多肽及其脂肪酸结合物，(2)明胶酶抑制剂的结构设计 A和-B，并确定其效力，(3)制定在选定的药物中传递抑制剂的策略 并评估它们在防止细胞侵袭方面的有效性。这些目标将是 通过运用合成有机化学，细胞和分子生物学技术完成的， 电子光谱学、酶动力学和热力学，以及分子模型构建方法。 拟议的研究结果将导致癌症的预防和/或治疗。

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.