Cyclo19,31[D-Cys19]-uPA19-31 Is a Potent Competitive Antagonist of the Interaction of Urokinase-Type Plasminogen Activator with Its Receptor (CD87)

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Abstract
Urokinasetype plasminogen activator (uPA) represents a central molecule in pericellular proteolysis and is implicated in a variety of physiological and pathophysiological processes such as tissue remodelling, wound healing, tumor invasion, and metastasis. uPA binds with high affinity to a specific cell surface receptor, uPAR (CD87), via a well defined sequence within the Nterminal region of uPA (uPA19-31). This interaction directs the proteolytic activity of uPA to the cell surface which represents an important step in tumor cell proliferation, invasion, and metastasis. Due to its fundamental role in these processes, the uPA/uPARsystem has emerged as a novel target for tumor therapy. Previously, we have identified a synthetic, cyclic, uPAderived peptide, cyclo19,31uPA19-31, as a lead structure for the development of low molecular weight uPAanalogues, capable of blocking uPA/uPARinteraction [Bürgle et al., Biol. Chem. 378 (1997), 231237]. We now searched for peptide variants of cyclo19,31uPA19-31 withelevated affinities for uPAR binding. Among other tasks, we performed a systematic Damino acid scan of uPA19-31, in which each of the 13 Lamino acids was individually substituted by the corresponding Damino acid. This led to the identification of cyclo19,31uPA19-31 as a potent inhibitor of uPA/uPARinteraction, displaying only a 20 to 40-fold lower binding capacity as compared to the naturally occurring uPARligands uPA and its aminoterminal fragment. Cyclo19,31uPA19-31 not only blocksbinding of uPA to uPAR but is also capable of efficiently displacing uPARbound uPA from the cell surface and to inhibit uPAmediated, tumor cellassociated plasminogen activation and fibrin degradation. Thus, cyclo19,31uPA19-31 represents a promising therapeutic agent to significantly affect the tumorassociated uPA/uPARsystem.