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Antimicrobial Agents and Chemotherapy, August 2005, p. 3474-3482, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3474-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Highly Potent Inhibition of Human Immunodeficiency Virus Type 1 Replication by TAK-220, an Orally Bioavailable Small-Molecule CCR5 Antagonist

Katsunori Takashima,1,2 Hiroshi Miyake,1,2 Naoyuki Kanzaki,1 Yoshihiko Tagawa,1 Xin Wang,2 Yoshihiro Sugihara,1 Yuji Iizawa,1 and Masanori Baba2*

Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Osaka 532-8686,1 Division of Antiviral Chemotherapy, Center for Chronic Viral Diseases, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan2

Received 17 December 2004/ Returned for modification 15 February 2005/ Accepted 4 April 2005

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.

* Corresponding author. Mailing address: 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. Phone: 81 99-275-5930. Fax: 81 99-275-5932. E-mail: baba{at}m.kufm.kagoshima-u.ac.jp.

Antimicrobial Agents and Chemotherapy, August 2005, p. 3474-3482, Vol. 49, No. 8
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.8.3474-3482.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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