Multivalent Design of Apoptosis-Inducing Bid-BH3 Peptide–Oligosaccharides Boosts the Intracellular Activity at Identical Overall Peptide Concentrations

Authors

  • Dr. Martin Richter,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin (Germany)
    2. Freie Universität Berlin, Institute of Chemistry and Biochemistry, Takustrasse 3, 14195 Berlin (Germany)
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    • These authors contributed equally to this work.

  • Alokta Chakrabarti,

    1. Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen (The Netherlands)
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    • These authors contributed equally to this work.

  • Dr. Ivo R. Ruttekolk,

    1. Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen (The Netherlands)
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  • Dr. Burkhard Wiesner,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin (Germany)
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  • Dr. Michael Beyermann,

    1. Leibniz Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin (Germany)
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  • Prof. Dr. Roland Brock,

    1. Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen (The Netherlands)
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  • Prof. Dr. Jörg Rademann

    Corresponding author
    1. Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Leipzig, Brüderstrasse 34, 04103 Leipzig (Germany), Fax: (+49) 341-97-36709
    2. Leibniz Institut für Molekulare Pharmakologie (FMP), Robert-Rössle-Strasse 10, 13125 Berlin (Germany)
    • Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, University of Leipzig, Brüderstrasse 34, 04103 Leipzig (Germany), Fax: (+49) 341-97-36709
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Abstract

Multivalent peptide–oligosaccharide conjugates were prepared and used to investigate the multivalency effect concerning the activity of Bid-BH3 peptides in live cells. Dextran oligosaccharides were carboxyethylated selectively in the 2-position of the carbohydrate units and activated for the ligation of N-terminally cysteinylated peptides. Ligation through maleimide coupling was found to be superior to the native chemical ligation protocol. Monomeric Bid-BH3 peptides were virtually inactive, whereas pentameric peptide conjugates induced apoptosis up to 20-fold stronger at identical peptide concentrations. Comparison of lowly multivalent and highly multivalent peptide dextrans proved a multivalency effect in life cells which was specific for the BH3 peptide sequence.

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