Studies on the Synthesis of Proteinase Inhibitors

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Abstract
Two heterodetic cyclic nonapeptides, (Ia: X=Ac, Y=NH2 Ib: X=H, Y=OH), which correspond to residues 14–22 in the sequence of Bowman-Birk inhibitor, have been synthesized by Merrifield's solid-phase method. Inhibitory activities of Ia and Ib on tryptic hydrolysis of amide and ester substrates were examined. When Gly2-Lys-Gly3 and Tos-Arg-OMe were used as substrates, the values of I50 for the peptide Ia were calculated to be 3.6 μM and 40 μM respectively. When Gly2-Lys-Gly3 was used as a substrate, the value of K1 was calculated to be 1.5 μM. Ia was hydrolyzed slowly by trypsin, losing the inhibitory activity. When the Lys-Ser bond of Ia was cleaved with trypsin, the modified Ia could not be regenerated by trypsin. The linear peptide S, S'-dicarboxamido methyl-Ia also was inactive and appeared to be a good substrate. Optical rotatory dispersion studies showed that the active fragments have characteristic conformations which were lost upon modification to inactive derivatives.

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