Pharmacological properties of peptides derived from stromal cell-derived factor 1: Study on human polymorphonuclear cells

Small compounds capable of blocking the stromal cell-derived factor 1 (SDF- 1) receptor CXCR4 may be potentially useful as anti-inflammatory, antialler gic, immunomodulatory, and antihuman immunodeficiency virus (HIV) agents. S DF-1-derived peptides have proven to target CXCR4 efficiently despite a 100 -fold lower affinity (or more) than SDF-1. Here we studied the binding and antiviral properties of a series of substituted SDF-1-derived N-terminal pe ptides and tested their functional effects on human polymorphonuclear cells , because these cells are very reactive to chemokines and chemoattractants. All peptides bound to CXCR4 and inhibited HIV entry in a functional assay on CD4(+) HeLa cells. A 10-residue substituted dimer, derived from the 5-14 sequence of SDF-1, displayed the high-est affinity for CXCR4 (K-i value of 290 nM, a reduction of only 15-fold compared with SDF-1) and was also the best competitor for HIV entry (IC50 value of 130 nM). Whereas most peptides displayed CXCR4-independent functional effects on human polymorphonuclear cells, including the modulation of calcium fluxes and the activation of sup eroxide anion production at high concentration (10 muM), the peptide dimer was devoid of these nonspecific effects at antiviral concentrations. Overal l, this study shows that appropriate modifications of SDF-1-derived N-termi nal peptides may ameliorate their binding and viral blocking properties wit hout generating significant unspecific side effects.