This proposal outlines a plan to conjugate an organic recognition element and reactive metal complex for the chemical modification of specific biological receptors. The guiding hypothesis for this research is that organoimido rhenium complexes can be designed to bind to an enzyme and chemically modify the active site, preventing catalysis. The organoimido linkage forms a strong, stable covalent bond between the recognition element and a high valent, Lewis acidic rhenium metal center. This metal is capable of coordinating to nucleophilic groups in the active site of the enzyme, thereby affecting catalysis.
The specific aims of this project are to synthesize a series of organoimido-rhenium inhibitors of thrombin, measure the inhibition of arginine substrate hydrolysis, investigate the mechanism to develop a model accounting for the inhibition, and then apply the model to design more efficient inhibitors. The thrombin inhibitors will contain a recognition element attached to a rhenium(V) metal center with an organoimido linkage. Recognition elements will match the arginine-binding selectivity of thrombin. A series of inhibitors include flexible and rigid linkages. Different substitution labile ligands will be used to vary the reactivity of the metal center. Enzyme inhibition will be measured using arginine substrates with spectroscopically observable cleavage products. Inhibition will be improved by modifying the recognition element, linkage, and metal center as suggested by mechanistic insight. The resulting thrombin inhibitors may be medically useful for preventing blood clotting. This general approach may also be applied to mechanistically different enzymatic systems and results in new types of inhibitor-based drugs.
Showing the most recent 10 out of 106 publications
