Proteolytic processing of human serum albumin generates EPI-X4, an endogenous antagonist of CXCR4.

The chemokine receptor CXCR4 is an important G protein-coupled receptor. Signaling via CXCL12 regulates a number of important biologic processes, including immune responses, organogenesis, or hematopoiesis. Dysregulation of CXCR4 signaling is associated with a variety of diseases, such as cancer development and metastasis, immunodeficiencies, or chronic inflammation. Here, we review our findings on endogenous peptide inhibitor of CXCR4 as a novel antagonist of CXCR4. This peptide is a 16-residue fragment of human serum albumin and was isolated as an inhibitor of CXCR4-tropic human immunodeficiency virus type 1 from a blood-derived peptide library. Endogenous peptide inhibitor of CXCR4 binds the second extracellular loop of CXCR4, thereby preventing engagement of CXCL12 and antagonizing the receptor. Consequently, endogenous peptide inhibitor of CXCR4 inhibits CXCL12-mediated migration of CXCR4-expressing cells in vitro, mobilizes hematopoietic stem cells, and suppresses inflammatory responses in vivo. We discuss the generation of endogenous peptide inhibitor of CXCR4, its relevance as biomarker for disease, and its role in human immunodeficiency virus/acquired immunodeficiency syndrome pathogenesis and cancer. Furthermore, we discuss why optimized endogenous peptide inhibitor of CXCR4 derivatives might have advantages over other CXCR4 antagonists.