title: Inhibition of T-tropic HIV strains by selective antagonization of the chemokine receptor CXCR4.
abstract: Bicyclams are a novel class of antiviral compounds that are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. Surprisingly, however, when the prototype compound AMD3100 was tested against M-tropic virus strains such as BaL, ADA, JR-CSF, and SF-162 in human peripheral blood mononuclear cells, the compound was completely inactive. Because of the specific and potent inhibitory effect of AMD3100 on T-tropic viruses, but not M-tropic viruses, it was verified that AMD3100 interacts with the CXC-chemokine receptor CXCR4, the main coreceptor used by T-tropic viruses. AMD3100 dose dependently inhibited the binding of a specific CXCR4 monoclonal antibody to SUP-T1 cells as measured by flow cytometry. It did not inhibit the binding of the biotinylated CC-chemokine macrophage inflammatory protein (MIP) 1alpha or MIP-1beta, ligands for the chemokine receptor CCR5 (the main coreceptor for M-tropic viruses). In addition, AMD3100 completely blocked (a) the Ca2+ flux at 100 ng/ml in lymphocytic SUP-T1 and monocytic THP-1 cells, and (b) the chemotactic responses of THP-1 cells induced by stromal cell-derived factor 1alpha, the natural ligand for CXCR4. Finally, AMD3100 had no effect on the Ca2+ flux induced by the CC-chemokines MIP-1alpha, regulated on activation normal T cell expressed and secreted (RANTES; also a ligand for CCR5), or monocyte chemoattractant protein 3 (a ligand for CCR1 and CCR2b), nor was it able to induce Ca2+ fluxes by itself. The bicyclams are, to our knowledge, the first low molecular weight anti-HIV agents shown to act as potent and selective CXCR4 antagonists.
authors.affiliation: Laboratory of Experimental Chemotherapy, Rega Institute for Medical Research, Leuven, Belgium. dominique.schols@rega.kuleuven.ac.be
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: S
authors.initials: S
authors.lastname: Struyf
authors.forename: J
authors.initials: J
authors.lastname: Van Damme
authors.forename: J A
authors.initials: JA
authors.lastname: Esté
authors.forename: G
authors.initials: G
authors.lastname: Henson
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D000918:Antibody Specificity; D001596:Benzylamines; D001666:Binding Sites, Antibody / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism; D002460:Cell Line; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D000080027:Cyclams; D016207:Cytokines / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006678:HIV / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D015498:HIV-2 / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000276:immunology; D013601:T-Lymphocytes / Q000821:virology*
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D000080027:Cyclams; D016207:Cytokines; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor; D002118:Calcium