title: An Apoptosis-Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5.
abstract: Multivalent ligands of death receptors hold particular promise as tumor cell-specific therapeutic agents because they induce an apoptotic cascade in cancerous cells. Herein, we present a modular approach to generate death receptor 5 (DR5) binding constructs comprising multiple copies of DR5 targeting peptide (DR5TP) covalently bound to biomolecular scaffolds of peptidic nature. This strategy allows for efficient oligomerization of synthetic DR5TP-derived peptides in different spatial orientations using a set of enzyme-promoted conjugations or recombinant production. Heptameric constructs based on a short (60-75 residues) scaffold of a C-terminal oligomerization domain of human C4b binding protein showed remarkable proapoptotic activity (EC50=3 nm) when DR5TP was ligated to its carboxy terminus. Our data support the notion that inter-ligand distance, relative spatial orientation and copy number of receptor-binding modules are key prerequisites for receptor activation and cell killing.
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Valldorf
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Fittler
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Lukas
authors.initials: L
authors.lastname: Deweid
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Aileen
authors.initials: A
authors.lastname: Ebenig
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Dickgiesser
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Sellmann
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Becker
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Zielonka
authors.affiliation: Helmholtz Institute for Pharmacological Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Empting
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Avrutina
authors.affiliation: Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany. kolmar@biochemie-tud.de.
authors.forename: Harald
authors.initials: H
authors.lastname: Kolmar
mesh_terms: D017209:Apoptosis; D006801:Humans; D010455:Peptides / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D010455:Peptides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human
keywords: C4BP; TRAIL mimicking peptide; apoptosis; death receptor 5; oligomerization