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. 2005 Aug;49(8):3474-82.
doi: 10.1128/AAC.49.8.3474-3482.2005.

Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist

Katsunori Takashima  1 , Hiroshi Miyake, Naoyuki Kanzaki, Yoshihiko Tagawa, Xin Wang, Yoshihiro Sugihara, Yuji Iizawa, Masanori Baba
Affiliations

Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist

Katsunori Takashima et al. Antimicrob Agents Chemother. 2005 Aug.

Abstract

TAK-220 is a member of a novel class of chemokine receptor antagonists and is highly specific to CCR5, as determined by receptor binding and calcium mobilization assays. The compound selectively inhibited coreceptor-mediated entry of human immunodeficiency virus type 1 (HIV-1) into host cells and HIV-1 infection mediated by CCR5. TAK-220 inhibited the replication of six CCR5-using (R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) with a mean 90% effective concentration of 13 nM. The anti-HIV-1 activity of TAK-220 was not affected by addition of high concentrations of human serum. It equally inhibited R5 HIV-1 replication in PBMCs obtained from eight different donors, irrespective of the levels of viral production. Furthermore, the anti-HIV-1 activity of TAK-220 was found to be subtype independent. TAK-220 did not induce CCR5 internalization but blocked the binding of two monoclonal antibodies that recognize the second extracellular loop of CCR5 in CCR5-expressing cells. These results suggest that TAK-220 selectively inhibits R5 HIV-1 replication by interfering with coreceptor-mediated entry of the virus into host cells. At a dose of 5 mg/kg of body weight, TAK-220 showed oral bioavailabilities of 9.5 and 28.9% in rats and monkeys, respectively. Thus, TAK-220 is a promising candidate for the treatment of HIV-1 infection.

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Figures

FIG. 1.
FIG. 1.
Chemical structure of TAK-220.
FIG. 2.
FIG. 2.
Effect of TAK-220 on the binding of (A) RANTES, (B) MIP-1α, and (C) MIP-1β to CCR5. The CCR5-expressing CHO cells were incubated with various concentrations of TAK-220 in the binding buffer containing 125I-labeled RANTES, MIP-1α, or MIP-1β. Binding reactions were performed at room temperature and were terminated by washing out the cell-free ligand with PBS. The cell-associated radioactivity was measured with a scintillation counter. The data represent the means ± SDs for triplicate wells.
FIG. 3.
FIG. 3.
Effect of TAK-220 on ligand binding to various chemokine receptors. The assay procedure for the inhibition of ligand binding to each chemokine receptor by TAK-220 was described in the legend to Fig. 2. The data represent the means ± SDs for triplicate wells.
FIG. 4.
FIG. 4.
Effect of TAK-220 on RANTES-induced Ca2+ mobilization in (A) CCR5- and (B) CCR1-expressing cells. CCR5- or CCR1-expressing HeLa cells were suspended in ECB buffer, loaded with 10 μM Fura-PE3AM for 60 min, washed twice, and resuspended in the same buffer. At 90 s after exposure to various concentrations of TAK-220, 20 nM RANTES was added, and the relative increase in cytoplasmic Ca2+ levels was monitored with a fluorescence spectrometer.
FIG. 5.
FIG. 5.
Effect of TAK-220 on anti-CCR5 MAb binding to CCR5-expressing cells. MOLT-4/CCR5 cells were incubated in the presence of TAK-220 (100 nM) and examined for the binding of anti-CCR5 MAbs. MAbs 45531.111 and 2D7 recognize ECL2 of CCR5, while MAb 3A9 recognizes the N terminus (N-term.) of CCR5. The MFI obtained in the absence of compound was regarded as 100% binding of each MAb. The data are expressed as the means ± SDs of three separate experiments.
FIG. 6.
FIG. 6.
Effect of TAK-220 on cell surface CCR5 expression. MOLT-4/CCR5 cells were incubated in the presence of various concentrations of either TAK-220 (•) or RANTES (○) for 3 h at 37°C. The expression of CCR5 on the cell surface was detected with the anti-CCR5 MAb 3A9. The MFI obtained in the absence of compound was regarded as 100% expression. The data are expressed as the means for triplicate tubes.
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