title: Exploring monovalent and multivalent peptides for the inhibition of FBP21-tWW.
abstract: The coupling of peptides to polyglycerol carriers represents an important route towards the multivalent display of protein ligands. In particular, the inhibition of low affinity intracellular protein-protein interactions can be addressed by this design. We have applied this strategy to develop binding partners for FBP21, a protein which is important for the splicing of pre-mRNA in the nucleus of eukaryotic cells. Firstly, by using phage display the optimized sequence WPPPPRVPR was derived which binds with K Ds of 80 μM and 150 µM to the individual WW domains and with a K D of 150 μM to the tandem-WW1-WW2 construct. Secondly, this sequence was coupled to a hyperbranched polyglycerol (hPG) that allowed for the multivalent display on the surface of the dendritic polymer. This novel multifunctional hPG-peptide conjugate displayed a K D of 17.6 µM which demonstrates that the new carrier provides a venue for the future inhibition of proline-rich sequence recognition by FBP21 during assembly of the spliceosome.
authors.affiliation: Institute for Chemistry and Biochemistry, Protein Biochemistry Group, Thielallee 63, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Lisa Maria
authors.initials: LM
authors.lastname: Henning
authors.affiliation: Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany.
authors.forename: Sumati
authors.initials: S
authors.lastname: Bhatia
authors.affiliation: Institute for Chemistry and Biochemistry, Protein Biochemistry Group, Thielallee 63, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Bertazzon
authors.affiliation: Institute for Chemistry, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Marczynke
authors.affiliation: Institute for Chemistry, Humboldt-Universität Berlin, Brook-Taylor-Str. 2, 12489 Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Seitz
authors.affiliation: Leibniz Institut für Molekulare Pharmakologie FMP, Robert-Rössle-Str.10, 13125 Berlin, Germany.|Institute of Medical Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Volkmer
authors.affiliation: Institute for Chemistry and Biochemistry, Freie Universität Berlin, Takustr. 3, 14195 Berlin, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Haag
authors.affiliation: Institute for Chemistry and Biochemistry, Protein Biochemistry Group, Thielallee 63, Freie Universität Berlin, 14195 Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
keywords: FBP21-tWW; isothermal titration calorimetry; multivalent polymers; polyglycerol peptide conjugates; proline-rich sequence recognition