Synthesis and structure of prolinal-containing peptides, and their use as specific inhibitors of prolyl endopeptidases.

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Abstract
Peptide aldehydes are potent inhibitors of serine and cysteine proteases. In the present work, N-benyloxycarbonyl (Z) dipeptides containing prolinal at the carboxyl terminus were synthesized as inhibitors of prolyl endopeptidases. Since no aldehyde proton was detected by proton nuclear magnetic resonance (1H-NMR) spectrometry, a cyclic structure was proposed for these peptides. Compounds with a Z-L-X-L-prolinal structure were strong inhibitors of prolyl endopeptidases from the ascidian, Halocynthia roretzi, and Flavobacterium meningosepticum. The potency was in the order of Z-L-Val-L-prolinal .simeq. Z-L-Ile-L-prolinal > Z-L-Phe-L-prolinal > Z-L-Ala-L-prolinal and IC50 values of 10-8-10-6 M order for both enzymes. Conversion of the aldehyde into an alcohol or an acid moiety resulted in a considerable decrease in the inhibitory activity. The diastereomers of Z-L-Phe-L-prolinal were much less inhibitory. This result is not compatible with the reported stereospecifity of the Flavobacterium enzyme for its substrates [T. Yoshimoto, R. Walter and D. Tsuru, J. Biol. Chem., 255, 4786 (1980)]. This implies that the open species binds preferentially to the enzyme active site.