Discovery and characterization of an endogenous CXCR4 antagonist PMID: 25921529

ADC Targets in Oncology

2026-04-10

Discovery and characterization of an endogenous CXCR4 antagonist

Cell Rep. 2015 May 5;11(5):737-47. doi: 10.1016/j.celrep.2015.03.061.

Onofrio Zirafi ¹ , Kyeong-Ae Kim ¹ , Ludger Ständker ² , Katharina B Mohr ¹ , Daniel Sauter ¹ , Anke Heigele ¹ , Silvia F Kluge ¹ , Eliza Wiercinska ³ , Doreen Chudziak ³ , Rudolf Richter ⁴ , Barbara Moepps ⁵ , Peter Gierschik ⁵ , Virag Vas ⁶ , Hartmut Geiger ⁶ , Markus Lamla ⁷ , Tanja Weil ⁷ , Timo Burster ⁸ , Andreas Zgraja ⁹ , Francois Daubeuf ¹⁰ , Nelly Frossard ¹⁰ , Muriel Hachet-Haas ¹¹ , Fabian Heunisch ¹² , Christoph Reichetzeder ¹² , Jean-Luc Galzi ¹¹ , Javier Pérez-Castells ¹³ , Angeles Canales-Mayordomo ¹⁴ , Jesus Jiménez-Barbero ¹⁴ , Guillermo Giménez-Gallego ¹⁴ , Marion Schneider ¹⁵ , James Shorter ¹⁶ , Amalio Telenti ¹⁷ , Berthold Hocher ¹² , Wolf-Georg Forssmann ¹⁸ , Halvard Bonig ³ , Frank Kirchhoff ¹⁹ , Jan Münch ²⁰

Affiliations

1. Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany.
2. Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany; PHARIS Biotec GmbH, 30625 Hannover, Germany.
3. German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany.
4. German Red Cross Blood Service Baden-Württemberg-Hessen and Institute for Transfusion Medicine and Immunohaematology, Goethe University, 60528 Frankfurt, Germany; Department of Internal Medicine, Clinic of Immunology, Hannover Medical School, 30625 Hannover, Germany.
5. Institute of Pharmacology and Toxicology, University of Ulm, 89081 Ulm, Germany.
6. Department of Dermatology and Allergic Diseases, University of Ulm, 89081 Ulm, Germany.
7. Institute of Organic Chemistry III, University of Ulm, 89081 Ulm, Germany.
8. Department of Neurosurgery, University of Ulm, 89081 Ulm, Germany.
9. PHARIS Biotec GmbH, 30625 Hannover, Germany.
10. UMR7200, Therapeutic Innovation Lab, CNRS-University of Strasbourg, Faculty of Pharmacy, and LabEx Medalis, 67401 Illkirch, France.
11. UMR7242, Biotechnology and Cellular Signaling, School of Biotechnology of Strasbourg, 67412 Illkirch, France.
12. Institute of Nutritional Science, University of Potsdam, 14558 Nuthetal-Potsdam, Germany.
13. Department of Chemistry, University San Pablo-CEU, 280040 Madrid, Spain.
14. Department of Physico-Chemical Biology, Centro de Investigaciones Biológicas, 28040 Madrid, Spain.
15. Experimental Anesthesiology Section, University Hospital Ulm, 89081 Ulm, Germany.
16. Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
17. J. Craig Venter Institute, La Jolla, CA 92037, USA.
18. Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; PHARIS Biotec GmbH, 30625 Hannover, Germany; Department of Internal Medicine, Clinic of Immunology, Hannover Medical School, 30625 Hannover, Germany.
19. Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany.
20. Institute of Molecular Virology, University of Ulm, 89081 Ulm, Germany; Ulm Peptide Pharmaceuticals, University of Ulm, 89081 Ulm, Germany. Electronic address: [email protected].

Abstract

CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 Antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for Chemokine Receptor regulation.