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      High-affinity urokinase receptor antagonists identified with bacteriophage peptide display.

      Proceedings of the National Academy of Sciences of the United States of America
      Amino Acid Sequence, Animals, Bacteriophage M13, metabolism, Base Sequence, Binding, Competitive, Cell Line, DNA, Humans, Molecular Sequence Data, Peptides, Receptors, Cell Surface, antagonists & inhibitors, Receptors, Urokinase Plasminogen Activator, Recombinant Proteins, Urokinase-Type Plasminogen Activator, Viral Proteins

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          Affinity selection of a 15-mer random peptide library displayed on bacteriophage M13 has been used to identify potent ligands for the human urokinase receptor, a key mediator of tumor cell invasion. A family of receptor binding bacteriophage ligands was obtained by sequentially and alternately selecting the peptide library on COS-7 monkey kidney cells and baculovirus-infected Sf9 insect cells overexpressing the human urokinase receptor. Nineteen peptides encoded by the random DNA regions of the selected bacteriophage were synthesized and tested in a urokinase receptor binding assay, where they competed with the labeled N-terminal fragment of urokinase with IC50 values ranging from 10 nM to 10 microM. All of the isolated peptides were linear and showed two relatively short conserved subsequences: LWXXAr (Ar = Y, W, F, or H) and XFXXYLW, neither of which is found in urokinase or its receptor. Competition experiments demonstrated that the most potent peptide, clone 20, prevented binding of bacteriophage displaying the urokinase receptor binding sequence (urokinase residues 13-32). In addition, this peptide blocked other apparently unrelated receptor binding bacteriophage, suggesting overlapping receptor interaction sites for all of these sequences. These results provide a demonstration of bacteriophage display identifying peptide ligands for a receptor expressed on cells and yield leads for the development of urokinase receptor antagonists.

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