Pharmacological Properties of Peptides Derived from Stromal Cell-Derived Factor 1: Study on Human Polymorphonuclear Cells
- Nikolaus Heveker1,
- Michèle Tissot1,
- Alain Thuret,
- Jens Schneider-Mergener2,
- Marc Alizon1,
- Monique Roch and
- Stefano Marullo1
- 1Department of Cell Biology, Institut Cochin de Génétique Moléculaire, Paris, France (N.H., M.T., O.M., M.A., S.M.); and 2Institut für Medzinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität, Berlin, Germany (J.S-M.)
Abstract
Small compounds capable of blocking the stromal cell-derived factor 1 (SDF-1) receptor CXCR4 may be potentially useful as anti-inflammatory, antiallergic, immunomodulatory, and anti-human immunodeficiency virus (HIV) agents. SDF-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 peptides 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 highest affinity for CXCR4 (Ki 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 superoxide anion production at high concentration (10 μM), the peptide dimer was devoid of these nonspecific effects at antiviral concentrations. Overall, this study shows that appropriate modifications of SDF-1–derived N-terminal peptides may ameliorate their binding and viral blocking properties without generating significant unspecific side effects.
Footnotes
-
Send reprint requests to: Stefano Marullo Département de Biologie Cellulaire, ICGM, Hôpital Cochin, 27 rue du Faubourg, Saint Jacques, 75014 Paris, France. E-mail:marullo{at}cochin.inserm.fr
-
This work was supported by Grants from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the University of Paris V, the Agence Nationale pour la Recherche contre le SIDA, the Association pour la Recherche contre le Cancer, and the Fondation pour la Recherche Médicale.
- Abbreviations:
- SDF-1
- stromal cell-derived factor 1
- HIV
- human immunodeficiency virus
- PMN
- neutrophil polymorphonuclear cells
- HBSS
- phenol red-free Hanks' balanced salt solution containing sodium hydrogen carbonate and calcium and magnesium salts
- IL-8
- interleukin-8
- Groα
- growth-related oncogene-α chemokine
- AM
- acetoxymethylester
- PTX
- pertussis toxin
- C5a
- complement fraction C5-a
- fMLP
- formyl-Met-Leu-Phe peptide
-
- Received September 21, 2000.
- Accepted February 16, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
