The urokinase plasminogen activator system consists of the serine protease urokinase (uPA), its cell surface-associated receptor (uPAR), plasminogen activator inhibitors (PAIs) and the proenzyme plasminogen (Plg).  uPA is responsible for the Plg activation to plasmin (Plm) by the Arg561-Val562 bond hydrolysis in Plg.

                Plm, the key enzyme of fibrinolysis, is a non-specific trypsin-like protease, which cleaves after numerous Lys or Arg bonds. It attacks fibronectin, fibrin/fibrinogen, clotting factors V/Va and VIII/VIIIa, latent TGF-β, IGF binding proteins and the zymogen forms of several metalloproteases. In contrast, uPA is a highly specific serine protease, which catalyses cleaving single Arg-X or Lys-X bonds in for example the hepatocyte growth factor, fibronectin, diphtheria toxin, uPAR and uPA itself. The two-chain active form of uPA is activated from a single chain precursor (prouPA) by plasmin or possibly via enzymes commonly enriched in cancer cells such as thiol cathepsins. uPA is unique in having its own high affinity cell-surface receptor uPAR. The urokinase receptor is focalized in the cell-cell connection and on the edge of invading cells. Thus, the uPA system plays a pivotal role in degradating and regenerating of the basement membrane which leads directly to tissue remodelling, invasiveness and angiogenesis. The binding of uPA to uPAR also initiates signalling cascades that does not require the uPA catalytic activity but only receptor occupancy. The expression of uPA and uPAR has been demonstrated in essentially every cancer type, such as gastric, colorectal, ovarian, breast, endometrial and prostate cancer.

We present the synthesis and the investigation of effect peptides of general formula H-D-Ser-AA-Arg-OH (AA = leucine, norleucine, izoleucine, valine, norvaline, α-metyloalanine, α-aminobutanoic acid, homoleucine, tert-leucine, neoglycine) on amidolytic activity of urokinase, thrombin, plasmin, trypsin, t-PA and kallikrein. We expected that the use of specific tripeptide sequence to urokinase would cause high urokinase selectivity [1, 2]. The peptides were synthesized on the solid phase manually using standard Fmoc-based strategy.

1. Markowska A., Bruzgo I., Midura-Nowaczek K., Int. J. Pept. Res. Ther., 14, 215-218, 2008.

2. Markowska A., Bruzgo I., Midura-Nowaczek K., J. Enz. Inh. Med. Chem., 25, 139-142, 2010.

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