N-TERMINAL PEPTIDES OF STROMAL CELL-DERIVED FACTOR-I WITH CXC CHEMOKINE RECEPTOR-4 AGONIST AND ANTAGONIST ACTIVITIES

Peptides corresponding to the N-terminal 9 residues of stromal cell-de rived 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 lymphocyt es and CEM cells and bound to CXC chemokine receptor 4 (CXCR4). The pe ptides had similar activities to SDF-1 but were less potent. Whereas n ative 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 1-1 7 and a 1-9 monomer analog were 4 and 36-fold, respectively, less pote nt than the 1-9 dimer, Both the chemotactic and calcium response of th e 1-9 dimer was inhibited by an antibody to CXCR4. The basis for the e nhanced 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] dim er, was found to be a CXCR4 antagonist, Overall this study shows that the N-terminal peptides are CXCR4 agonists or antagonists, and these c ould be leads for high affinity ligands.