N-terminal Peptides of Stromal Cell-derived Factor-1 with CXC Chemokine Receptor 4 Agonist and Antagonist Activities

Abstract Peptides corresponding to the N-terminal 9 residues of stromal cell-derived factor-1 (SDF-1) have SDF-1 activity. SDF-1, 1–8, 1–9, 1–9 dimer, and 1–17 induced intracellular calcium and chemotaxis in T lymphocytes and CEM cells and bound to CXC chemokine receptor 4 (CXCR4). The peptides had similar activities to SDF-1 but were less potent. Whereas native SDF-1 had half-maximal chemoattractant activity at 5 nm, the 1–9 dimer required 500 nm and was therefore 100-fold less potent. The 1–17 and a 1–9 monomer analog were 4- and 36-fold, respectively, less potent than the 1–9 dimer. Both the chemotactic and calcium response of the 1–9 dimer was inhibited by an antibody to CXCR4. The basis for the enhanced activity of the dimer form of SDF-1, 1–9 is uncertain, but it could involve an additional fortuitous binding site on the 1–9 peptide in addition to the normal SDF-1, 1–9 site. A 1–9 analog, 1–9[P2G] dimer, was found to be a CXCR4 antagonist. Overall this study shows that the N-terminal peptides are CXCR4 agonists or antagonists, and these could be leads for high affinity ligands.