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Angew Chem Int Ed Engl. 2016 Apr 11;55(16):5085-9. doi: 10.1002/anie.201511894. Epub 2016 Mar 15.

An Apoptosis-Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5.

Author information

1
Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany.
2
Helmholtz Institute for Pharmacological Research Saarland (HIPS), Universitätscampus E8 1, 66123, Saarbrücken, Germany.
3
Clemens-Schöpf-Institut für Organische Chemie und Biochemie, Technische Universität Darmstadt, Alarich-Weiss-Strasse 4, 64287, Darmstadt, Germany. kolmar@biochemie-tud.de.

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.

KEYWORDS:

C4BP; TRAIL mimicking peptide; apoptosis; death receptor 5; oligomerization

PMID:
26991930
DOI:
10.1002/anie.201511894
[Indexed for MEDLINE]

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