A CCR5 antagonist
TAK-220 is an orally bioavailable antagonist of chemokine (C-C motif) receptor 5 (CCR5).1 It binds to CCR5 (IC50 = 3.5 nM for the human receptor in CHO cells), but not CCR1, CCR2b, CCR3, CCR4, or CCR7.1,2 TAK-220 inhibits the binding of chemokine (C-C motif) ligand 5 (CCL5) and CCL3 to CCR5 (IC50s = 3.5 and 1.4 nM, respectively) but does not inhibit binding of CCL4.2 It inhibits HIV-1 envelope-mediated membrane fusion in a macrophage (M-tropic) R5, but not in a T cell (T-tropic) X4, strain of HIV-1 (IC50s = 0.42 and >1,000 nM, respectively). TAK-220 inhibits the replication of six strains of R5 HIV-1 clinical isolates (EC90 overall mean = 13 nM) and the R5 JR-FL laboratory-adapted strain (EC50 = 0.6 nM), but not of X4 HIV-1 clinical isolates or the X4 IIIB laboratory-adapted strain (EC50s = >10,000 nM for both), in human peripheral blood mononuclear cells (PBMCs).
1.Imamura, S., Ichikawa, T., Nishikawa, Y., et al.Discovery of a piperidine-4-carboxamide CCR5 antagonist (TAK-220) with highly potent Anti-HIV-1 activityJ. Med. Chem.49(9)2784-2793(2006) 2.Takashima, K., Miyake, H., Kanzaki, N., et al.Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonistAntimicrob. Agents Chemother.49(8)3474-3482(2005)
Cell experiment: | PHA-stimulated PBMCs are inoculated with 1,000 to 1,400 CCID50s of R5 HIV-1 (JR-FL) or X4 HIV-1 (IIIB) or with 13 to 55 ng of p24 of HIV-1 clinical isolates per 4 × 106 cells and incubated for 4 h. The cells are washed to remove unadsorbed viral particles and seeded into a 96-well plate (2 × 105 cells/well) with culture medium containing various concentrations of TAK-220. The effects of high concentrations of human serum (HS) on the anti-HIV-1 activity of TAK-220 are examined with RPMI 1640 medium supplemented with either 20% FBS alone or 40% human type AB serum plus 10% FBS, 100 U/mL recombinant human interleukin 2, and antibiotics. On day 4 after infection, the cells are subcultured at 1:2 with culture medium containing the same concentrations of the test compounds. On day 7 after infection, the culture supernatants are collected and their p24 antigen levels are determined with a p24 antigen enzyme-linked immunosorbent assay kit[1]. |
参考文献: [1]. Takashima K, et al. Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist. Antimicrob Agents Chemother. 2005 Aug;49(8):3474-82. | |
动态评分
0.0