Low molecular weight two-chain urokinase is a 33-kD plasminogen activator, which has no innate affinity for fibrin and consequently, its use to facilitate lysis of blood clots may lead to systemic activation of plasminogen. In order to impart clot affinities to this urokinase form (UK) we have generated two novel fibrin-binding derivatives by partially reducing UK and exchanging the native disulfide-linked peptide A with peptide A analogs. The peptide A analogs contained the fibrin-adherent fibrin-derived sequences, GPRP (derived from positions 17-20 of the fibrinogen alpha chain) or QAGDV (407-411 sequence of the fibrinogen gamma chain), each coupled through amino-hexanoic acid to a synthetic peptide, LKFQCGQK, containing the Leu 144-Lys 158 sequence of the urinary plasminogen activator A Chain. The resultant derivatives contained about 0.4 moles peptide analog/mole UK, were 75% active toward synthetic UK substrates, and were recovered in a nearly 80% yield. The two fibrin peptide derivatives had a five-fold greater affinity for the clots.
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