N-terminal peptides of stromal cell-derived factor-1 with CXC chemokine receptor 4 agonist and antagonist activities.
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.
Theodor-Kocher Institute, University of Bern, CH 3000 Bern, Switzerland.
P
P
Loetscher
J H
JH
Gong
B
B
Dewald
M
M
Baggiolini
I
I
Clark-Lewis
D000595:Amino Acid Sequence; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000737:chemistry*; D002630:Chemotactic Factors / Q000494:pharmacology; D019281:Dimerization; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017154:Stromal Cells / Q000737:chemistry*
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D010446:Peptide Fragments; D019718:Receptors, CXCR4