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Journal of Virology, August 2004, p. 8654-8662, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8654-8662.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Spirodiketopiperazine-Based CCR5 Inhibitor Which Preserves CC-Chemokine/CCR5 Interactions and Exerts Potent Activity against R5 Human Immunodeficiency Virus Type 1 In Vitro

Kenji Maeda,1,2 Hirotomo Nakata,1,2 Yasuhiro Koh,1,2 Toshikazu Miyakawa,2 Hiromi Ogata,1,2 Yoshikazu Takaoka,3 Shiro Shibayama,3 Kenji Sagawa,3 Daikichi Fukushima,3 Joseph Moravek,4 Yoshio Koyanagi,5 and Hiroaki Mitsuya1,2,6*

Department of Hematology,1 Department of Infectious Diseases, Kumamoto University School of Medicine, Kumamoto 860-8556,2 Minase Research Institute, Ono Pharmaceutical Co. Ltd., Osaka 618-8585,3 Department of Virology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan,5 Moravek Biochemicals, Inc., Brea, California 92821,4 Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, Bethesda, Maryland 208926

Received 6 January 2004/ Accepted 31 March 2004

We identified a novel spirodiketopiperazine (SDP) derivative, AK602/ONO4128/GW873140, which specifically blocked the binding of macrophage inflammatory protein 1{alpha} (MIP-1{alpha}) to CCR5 with a high affinity (Kd of {approx}3 nM), potently blocked human immunodeficiency virus type 1 (HIV-1) gp120/CCR5 binding and exerted potent activity against a wide spectrum of laboratory and primary R5 HIV-1 isolates, including multidrug-resistant HIV-1 (HIV-1MDR) (50% inhibitory concentration values of 0.1 to 0.6 nM) in vitro. AK602 competitively blocked the binding to CCR5 expressed on Chinese hamster ovary cells of two monoclonal antibodies, 45523, directed against multidomain epitopes of CCR5, and 45531, specific against the C-terminal half of the second extracellular loop (ECL2B) of CCR5. AK602, despite its much greater anti-HIV-1 activity than other previously published CCR5 inhibitors, including TAK-779 and SCH-C, preserved RANTES (regulated on activation normal T-cell expressed and secreted) and MIP-1ß binding to CCR5+ cells and their functions, including CC-chemokine-induced chemotaxis and CCR5 internalization, while TAK-779 and SCH-C fully blocked the CC-chemokine/CCR5 interactions. Pharmacokinetic studies revealed favorable oral bioavailability in rodents. These data warrant further development of AK602 as a potential therapeutic for HIV-1 infection.

* Corresponding author. Mailing address: Department of Hematology, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan. Phone: 81-96-373-5156. Fax: 81-96-363-5265. E-mail: hmitsuya{at}helix.nih.gov.

Journal of Virology, August 2004, p. 8654-8662, Vol. 78, No. 16
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.16.8654-8662.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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