Synthesis and properties of cyclic peptides containing the activation site of plasminogen

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Abstract
The activation of plasminogen results from proteolytic cleavage of the Arg560.sbd.Val561 bond by plasminogen activators. This region of the zymogen occurs in a small disulfide loop that must restrict the conformation around this bond. The nonapeptide sequence .**GRAPHIC**. of plasminogen containing the activator sensitive arginyl valine bond was synthesized by carbodiimide coupling of Boc[butoxycarbonyl]-Cys-Pro-Gly-OH(S-4-methylbenzyl) to NH2-Arg(NO2)-Val-Val-Gly-Gly-Cys-NH2(S-4-methylbenzyl), followed by HF treatment and K3Fe(CN)6 oxidation to form a disulfide bond. Purified peptide was not a substrate for urokinase (UK) or plasminogen activator (PA) but possessed a slightly inhibitory activity towards PA. Addition of a lysine to the N-terminus of the nonapeptide yielded a decapeptide sequence of plasminogen that was a better substrate for UK but not for PA. The decapeptide inhibits PA slightly but not UK. Active site geometry for PA apparently must be more restrictive than that of UK and that other regions may be involved in the productive interactions with the activators, inducing a better fit of the cyclic peptide loop.