An Apoptosis-Inducing Peptidic Heptad That Efficiently Clusters Death Receptor 5.
- Resource Type
- Article
- Authors
- Valldorf, Bernhard; Fittler, Heiko; Deweid, Lukas; Ebenig, Aileen; Dickgiesser, Stephan; Sellmann, Carolin; Becker, Janine; Zielonka, Stefan; Empting, Martin; Avrutina, Olga; Kolmar, Harald
- Source
- Angewandte Chemie International Edition. 4/11/2016, Vol. 55 Issue 16, p5085-5089. 5p.
- Subject
- *PEPTIDES
*LIGANDS (Chemistry)
*CANCER cell culture
*OLIGOMERIZATION
*CARRIER proteins
- Language
- ISSN
- 1433-7851
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 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. [ABSTRACT FROM AUTHOR]