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Mapping the binding site of tissue kallikrein: preparation and testing of all possible substrate analog inhibitors homologous with the sequence of kininogen between Ser386 and Gln392.

Programs aimed at converting peptide inhibitors of proteolytic enzymes into more traditional drug structures require an understanding of the role played by the individual amino acid residues in the inhibitor. To this end, all possible substrate analogues occurring within the sequence Ser386-Pro-Phe-Arg-Ser-Val-Gln392 from bovine kininogen were synthesized and tested as inhibitors of tissue kallikrein (EC 3.4.21.35, beta-PPK). Of the 21 sequences which can be formed from the heptapeptide, 11 have inhibitory constants which could be measured in the chromogenic assay employed in these studies. No dipeptide and only one tripeptide, Ac-Phe-Arg-Ser-NH2 (Ki = 718 microM), measurably inhibits the enzyme. All longer peptides inhibit beta-PPK. The heptapeptide Ac-Ser-Pro-Phe-Arg-Ser-Val-Gln-NH2 is the most effective inhibitor in this series (Ki = 101 microM). Each amino acid residue in the sequence appears to alter binding in a relatively independent manner. The N-terminal seryl residue (P4) and the prolyl residue (P3) slightly improve the Ki of the various inhibitors. The phenylalanyl residue at P2 appears to have a more pronounced effect on Ki. The arginyl residue at P1 and the seryl residue at P1' appear to be the most important residues in the inhibitory sequence. They contribute approximately one-third and one-fourth of the binding energy to the interaction between the substrate analogues and beta-PPK, respectively. The valyl residue at P2', and the C-terminal glutaminyl residue improve Ki of each of the peptides tested. Almost 80% of the binding energy of the substrate analogue inhibitors comes from the core sequence Phe-Arg-Ser which occurs between P2 and P1'. Molecular models developed from the Chen-Bode coordinates of the aprotinin-beta-PPK complex have been used to interpret the results of these studies.