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An Apoptosis‐Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5
Author(s) -
Valldorf Bernhard,
Fittler Heiko,
Deweid Lukas,
Ebenig Aileen,
Dickgiesser Stephan,
Sellmann Carolin,
Becker Janine,
Zielonka Stefan,
Empting Martin,
Avrutina Olga,
Kolmar Harald
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201511894
Subject(s) - receptor , peptide , recombinant dna , chemistry , ligand (biochemistry) , programmed cell death , microbiology and biotechnology , apoptosis , stereochemistry , biochemistry , biology , gene
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 (EC 50 =3 n m ) 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.