Current Biology
Volume 8, Issue 7, 26 March 1998, Pages 369-376
Journal home page for Current Biology

Research Paper
Dissociation of the signalling and antiviral properties of SDF-1-derived small peptides

https://doi.org/10.1016/S0960-9822(98)70155-1Get rights and content
Under an Elsevier user license
open archive

Abstract

Background: The chemokine receptor CXCR4 (a receptor for the Cys-X-Cys class of chemokines) is a CD4-associated coreceptor for T-cell-tropic strains of human immunodeficiency virus 1 (HIV-1) and represents a target for antiviral therapy. Infection by T-tropic HIV-1 can be blocked by stromal-cell-derived factor-1 (SDF-1), the natural ligand of CXCR4. The broad variety of cells expressing CXCR4 and the perturbations observed in mice deficient for SDF-1 suggest that antiviral compounds antagonizing the signalling activity of CXCR4 might have severe side effects in vivo. Compounds that interfere selectively with HIV entry and not with SDF-1 signalling would therefore be useful.

Results: A series of peptides, each of 13 residues, spanning the whole SDF-1α sequence were tested for their ability to block HIV-1 infection. The antiviral and signalling properties of SDF-1 were retained by a peptide corresponding to its amino terminus. Removal of the first two residues resulted in an antiviral antagonist of the SDF-1–CXCR4 signalling pathway. We prepared 234 single-substitution analogues and identified one antiviral analogue that had drastically reduced agonistic or antagonistic properties. The antiviral peptides competed with the monoclonal antibody 12G5 for CXCR4 binding. Their antiviral activity seems to be due to receptor occupancy rather than induction of receptor endocytosis.

Conclusions: The amino terminus of the SDF-1 chemokine is sufficient for signal transduction via CXCR4 and for inhibition of HIV-1 entry, but these activities could be dissociated in a peptide analogue. This peptide represents a lead molecule for the design of low molecular weight antiviral drugs.

Cited by (0)

N Heveker and M Alizon, Inserm U.332, Institut Cochin de Génétique Moléculaire, 22 rue Méchain, 75014 Paris, France.

M Montes and A Trautmann, CNRS URA 7627, CERVI, Hôpital Pitié-Salpêtrière, 75013 Paris, France.

L Germeroth, Jerini Bio Tools GmbH, 12489 Berlin, Germany.

A Amara, Immunologie Virale, Institut Pasteur, 75015 Paris, France.

J Schneider-Mergener, Institut für Medizinische Immunologie, Universitätsklinikum Charité, Humboldt-Universität, 10098 Berlin, Germany.

E-mail address for N Heveker (corresponding author): [email protected].