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

Abstract

The ␤-chemokine receptor CCR5 is considered to be an attractive target for inhibition of macrophagetropic (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 (M r 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 Ca 2؉ signaling at nanomolar concentrations. The inhibition of ␤-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.

SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infectionin vitroandin vivo

“…This potency is comparable with or greater than that of TAK-779, a small molecule inhibitor of CCR5 that has previously been described (29). However, unlike TAK-779, SCH-C is orally bioavailable and has no cross-reactivity with CCR2 or other chemokine receptors.…”

“…Several inhibitors of CCR5-mediated HIV-1 entry have been shown to prevent R5 virus infection in vitro. These include modified chemokines (25,26), monoclonal antibodies to CCR5 (27,28), and a small molecule antagonist, TAK-779 (29), that binds within a cavity in the transmembrane domains of CCR5 (30).…”

Impact of Mutations in the Coreceptor Binding Site on Human Immunodeficiency Virus Type 1 Fusion, Infection, and Entry Inhibitor Sensitivity

“…Having introduced mutations into conserved regions of YU-2 that reduced CCR5 binding and in some cases altered fusion efficiency and kinetics, we next determined the impact of these changes on the sensitivity of each Env to a CD4-specific antibody, a small-molecule inhibitor of CCR5 binding (TAK-779) (2), and the fusion inhibitors enfuvirtide and T-1249. None of the gp120 mutations significantly affected the ability of a monoclonal antibody to CD4 to prevent membrane fusion (Fig.…”

High-Throughput HIV–Cell Fusion Assay for Discovery of Virus Entry Inhibitors

“…[13][14][15][16][17][18][19][20][21][22][23][24] HTS for smallmolecule inhibitors competing with the chemokine (RANTES) binding to CCR5 has led to the identification of identified coreceptor antagonists that effectively blocked fusion of CCR5-tropic viruses: maraviroc, Sch-C, and TAK-779. [10][11][12] These narrowly focused readouts provide a powerful means to identify specific inhibitors of a given step of the virus entry, but exclude all other targets for inhibition of HIV-1 fusion.…”

“…In the final 6-helix bundle structure (6HB), three HR1 and three HR2 coalesce forming a highly stable antiparallel helical bundle. A number of small-molecule inhibitors of HIV-1 fusion that interfere with CD4-induced conformational changes in gp120, 8,9 coreceptor binding, [10][11][12] and the gp41 6HB formation [13][14][15][16][17][18][19][20][21][22][23][24] have been identified by high-throughput screening (HTS). Currently, only two HIV-1 fusion inhibitors (enfuvirtide and maraviroc) have been approved for clinical use.…”