ENZYME-CONTROLLED MOLECULAR RECOGNITION - SELECTIVE TARGETING OF TRYPSIN WITH A SUBSTRATE-INHIBITOR SUPRAMOLECULAR COMPLEX

We have synthesized and studied the host compound (1) that forms a non covalent complex (K = 480 +/- 30 M-1) with 1,4-diamidinobenzene (2) at pD 8.0 in D2O. Guest 2 has been shown to inhibit the proteases specif ic for cationic side chains (Ki values for thrombin,plasmin, and tryps in being 1.0 +/- 0.4, 0.6 +/- 0.1, and 0.88 +/- 0.07 mM, respectively) . Host 1 and the 1.2 complex are shown to undergo the trypsin-catalyze d cleavage that results in the increased concentration of the free for m of 2 and, therefore, induces the enzyme inhibition. Plasmin and thro mbin are shown to cleave I at a significantly lower rate than trypsin. Thus, the complex of 1 with 2 represents the first example of a selec tive enzyme-sensitive supramolecular system capable of enzyme targetin g through a ''trojan horse''-type mechanism in which a bioactive compo und acts on the same molecule that provides its release from a deliver y system.