title: Phosphopeptides with improved cellular uptake properties as ligands for the polo-box domain of polo-like kinase 1.
abstract: Human polo-like kinase 1 (Plk1) is involved in cell proliferation and overexpressed in a broad variety of different cancer types. Due to its crucial role in cancerogenesis Plk1 is a potential target for diagnostic and therapeutic applications. Peptidic ligands can specifically interact with the polo-box domain (PBD) of Plk1, a C-terminal located phosphoepitope binding motif. Recently, phosphopeptide MQSpTPL has been identified as ligand with high binding affinity. However, a radiolabeled version of this peptide showed only insufficient cellular uptake. The present study investigated peptide dimers consisting of PBD-targeting phosphopeptide MQSpTPL and a cell-penetrating peptide (CPP) moiety. The new constructs demonstrate superior uptake in different cancer cell-lines compared to the phosphopeptide alone. Furthermore, we could demonstrate binding of phosphopeptide-CPP dimers to PBD of Plk1 making the compounds interesting leads for the development of molecular probes for imaging Plk1 in cancer.
authors.affiliation: Institute of Radiopharmacy, Helmholtz Center Dresden-Rossendorf, Dresden, Germany.
authors.forename: Susan
authors.initials: S
authors.lastname: Richter
authors.forename: Ines
authors.initials: I
authors.lastname: Neundorf
authors.forename: Kristin
authors.initials: K
authors.lastname: Loebner
authors.forename: Martin
authors.initials: M
authors.lastname: Gräber
authors.forename: Thorsten
authors.initials: T
authors.lastname: Berg
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.forename: Joerg
authors.initials: J
authors.lastname: Steinbach
authors.forename: Jens
authors.initials: J
authors.lastname: Pietzsch
authors.forename: Frank
authors.initials: F
authors.lastname: Wuest
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D008024:Ligands; D010748:Phosphopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D000097869:Polo-Like Kinase 1
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D008024:Ligands; D010748:Phosphopeptides; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1