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Urokinasetype plasminogen activator (uPA) representsa central molecule in pericellular proteolysis and is implicated in a varietyof physiological and pathophysiological processes such as tissue remodelling,wound healing, tumor invasion, and metastasis. uPA binds with high affinity toa specific cell surface receptor, uPAR (CD87), via a well defined sequencewithin the Nterminal region of uPA (uPA19-31). This interaction directs theproteolytic activity of uPA to the cell surface which represents an importantstep in tumor cell proliferation, invasion, and metastasis. Due to itsfundamental role in these processes, the uPA/uPARsystem has emerged as a noveltarget for tumor therapy. Previously, we have identified a synthetic, cyclic,uPAderived peptide, cyclo19,31uPA19-31, as a lead structure for the developmentof low molecular weight uPAanalogues, capable of blocking uPA/uPARinteraction[Bürgle et al., Biol. Chem. 378 (1997), 231237]. We now searched for peptidevariants of cyclo19,31uPA19-31 withelevated affinities for uPAR binding. Amongother tasks, we performed a systematic Damino acid scan of uPA19-31, in whicheach of the 13 Lamino acids was individually substituted by the correspondingDamino acid. This led to the identification of cyclo19,31uPA19-31 as a potentinhibitor of uPA/uPARinteraction, displaying only a 20 to 40-fold lower bindingcapacity as compared to the naturally occurring uPARligands uPA and itsaminoterminal fragment. Cyclo19,31uPA19-31 not only blocksbinding of uPA touPAR but is also capable of efficiently displacing uPARbound uPA from the cellsurface and to inhibit uPAmediated, tumor cellassociated plasminogen activationand fibrin degradation. Thus, cyclo19,31uPA19-31 represents a promisingtherapeutic agent to significantly affect the tumorassociateduPA/uPARsystem.

biological chemistry

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