title: A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity.
abstract: The beta-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication because individuals having a nonfunctional receptor (a homozygous 32-bp deletion in the CCR5 coding region) are apparently normal but resistant to infection with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compound with a small molecular weight (Mr 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to CCR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ signaling at nanomolar concentrations. The inhibition of beta-chemokine receptors by TAK-779 appeared to be specific to CCR5 because the compound antagonized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Consequently, TAK-779 displayed highly potent and selective inhibition of R5 HIV-1 replication without showing any cytotoxicity to the host cells. The compound inhibited the replication of R5 HIV-1 clinical isolates as well as a laboratory strain at a concentration of 1.6-3.7 nM in peripheral blood mononuclear cells, though it was totally inactive against T-cell line-tropic (CXCR4-using or X4) HIV-1.
mesh_terms: D000577:Amides / Q000494:pharmacology*; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001667:Binding, Competitive; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D018946:Chemokine CCL5 / Q000378:metabolism; D006224:Cricetinae; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects