title: Highly potent inhibition of human immunodeficiency virus type 1 replication by TAK-220, an orally bioavailable small-molecule CCR5 antagonist.
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.
authors.affiliation: Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8544, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyake
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Tagawa
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Sugihara
authors.forename: Yuji
authors.initials: Y
authors.lastname: Iizawa
authors.forename: Masanori
authors.initials: M
authors.lastname: Baba
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001682:Biological Availability; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008297:Male; D008561:Membrane Fusion / Q000187:drug effects; D051381:Rats; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D019707:Receptors, Chemokine