Catalysis and Inhibition of Gelatinases

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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.