title: Novel peptide inhibitors of human kallikrein 2.
abstract: Human kallikrein 2 (hK2) is a serine protease produced by the secretory epithelial cells in the prostate. Because hK2 activates several factors participating in proteolytic cascades that may mediate metastasis of prostate cancer, modulation of the activity of hK2 is a potential way of preventing tumor growth and metastasis. Furthermore, specific ligands for hK2 are potentially useful for targeting and imaging of prostate cancer and for assay development. We have used enzymatically active recombinant hK2 captured by a monoclonal antibody exposing the active site of the enzyme to screen phage display peptide libraries. Using libraries expressing 10 or 11 amino acids long linear peptides, we identified six different peptides binding to hK2. Three of these were shown to be specific and efficient inhibitors of the enzymatic activity of hK2 toward a peptide substrate. Furthermore, the peptides inhibited the activation of the proform of prostate-specific antigen by hK2. Amino acid substitution analyses revealed that motifs of six amino acids were required for the inhibitory activity. These peptides are potentially useful for treatment and targeting of prostate cancer.
authors.affiliation: Department of Clinical Chemistry, Helsinki University Central Hospital, Biomedicum, FIN-00290 Helsinki, Finland.
authors.forename: Can
authors.initials: C
authors.lastname: Hekim
authors.forename: Jari
authors.initials: J
authors.lastname: Leinonen
authors.forename: Ale
authors.initials: A
authors.lastname: Närvänen
authors.forename: Hannu
authors.initials: H
authors.lastname: Koistinen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.forename: Erkki
authors.initials: E
authors.lastname: Koivunen
authors.forename: Ville
authors.initials: V
authors.lastname: Väisänen
authors.forename: Ulf-Håkan
authors.initials: UH
authors.lastname: Stenman
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001665:Binding Sites; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008969:Molecular Sequence Data; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000628:therapy; D011485:Protein Binding; D011994:Recombinant Proteins / Q000737:chemistry; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D019151:Peptide Library; D010455:Peptides; D011994:Recombinant Proteins; D020840:Tissue Kallikreins