A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity

The beta-chemokine receptor CCR5 is considered to be an attractive target f or inhibition of macrophage-tropic (CCR5-using or R5) HIV-1 replication bec ause individuals having a nonfunctional receptor (a homozygous 32-bp deleti on in the CCR5 coding region) are apparently normal but resistant to infect ion with R5 HIV-1. In this study, we found that TAK-779, a nonpeptide compo und with a small molecular weight (M-r 531.13), antagonized the binding of RANTES (regulated on activation, normal T cell expressed and secreted) to C CR5-expressing Chinese hamster ovary cells and blocked CCR5-mediated Ca2+ s ignaling at nanomolar concentrations. The inhibition of beta-chemokine rece ptors by TAK-779 appeared to be specific to CCR5 because the compound antag onized CCR2b to a lesser extent but did not affect CCR1, CCR3, or CCR4. Con sequently, TAK-779 displayed highly potent and selective inhibition of R5 H IV-I replication without showing any cytotoxicity to the host cells. The co mpound 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 mon onuclear cells, though it was totally inactive against T-cell line-tropic ( CXCR4-using or X4) HIV-1.