title: Bicyclams, a class of potent anti-HIV agents, are targeted at the HIV coreceptor fusin/CXCR-4.
abstract: Bicyclams are a novel class of antiviral compounds which are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. The prototype compound, AMD3100, has an IC50 of 1-10 ng/ml, which is a least 100,000 fold lower than the cytotoxic concentration. AMD3100 does not inhibit virus binding to the CD4 receptor and based on time-of-addition experiments, has been assumed to interact with the HIV fusion-uncoating process. Resistance of HIV-1 strains to AMD3100 is associated with the accumulation of several mutations in the viral envelope glycoprotein gp120. Here, we demonstrate that AMD3100 interacts with fusin (CXCR-4), the coreceptor used by T-tropic viruses to infect the target cells. The replication of NL4-3 wild type virus and NL4-3 dextran sulfate-resistant virus was inhibited by the CXC-chemokine, stromal cell-derived factor 1 (SDF-1), the natural ligand for CXCR-4. In contrast, the replication of the HIV-1 NL4-3 AMD3100-resistant virus was no longer inhibited by SDF-1. The bicyclams are the first low-molecular-weight anti-HIV agents shown to interact with the coreceptor for T-tropic viruses.
authors.affiliation: Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Schols
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*; D001596:Benzylamines; D002460:Cell Line; D002478:Cells, Cultured; D000080027:Cyclams; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D006678:HIV / Q000187:drug effects* / Q000378:metabolism*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D008565:Membrane Proteins / Q000187:drug effects*; D019718:Receptors, CXCR4; D015728:Receptors, HIV / Q000187:drug effects*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D008565:Membrane Proteins; D019718:Receptors, CXCR4; D015728:Receptors, HIV; D019204:GTP-Binding Proteins; C088327:plerixafor