DISSOCIATION OF THE SIGNALING AND ANTIVIRAL PROPERTIES OF SDF-1-DERIVED SMALL PEPTIDES

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 ta rget 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 ob served in mice deficient for SDF-1 suggest that antiviral compounds an tagonizing the signalling activity of CXCR4 might have severe side eff ects 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-1 alpha sequ ence were tested for their ability to block HIV-1 infection. The antiv iral and signalling properties of SDF-1 were retained by a peptide cor responding to its amino terminus. Removal of the first two residues re sulted in an antiviral antagonist of the SDF-1-CXCR4 signalling pathwa y. We prepared 234 single-substitution analogues and identified one an tiviral analogue that had drastically reduced agonistic or antagonisti c properties. The antiviral peptides competed with the monoclonal anti body 12G5 for CXCR4 binding. Their antiviral activity seems to be due to receptor occupancy rather than induction of receptor endocytosis. C onclusions: The amino terminus of the SDF-1 chemokine is sufficient fo r signal transduction via CXCR4 and for inhibition of HIV-1 entry, but these activities could be dissociated in a peptide analogue. This pep tide represents a lead molecule for the design of low molecular weight antiviral drugs.