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Antimicrobial Agents and Chemotherapy, December 2001, p. 3538-3543, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3538-3543.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Inhibitory Effects of Small-Molecule CCR5 Antagonists on Human Immunodeficiency Virus Type 1 Envelope-Mediated Membrane Fusion and Viral Replication

Katsunori Takashima,1,dagger Hiroshi Miyake,2 Rika A. Furuta,3 Jun-Ichi Fujisawa,3 Yuji Iizawa,2 Naoyuki Kanzaki,4 Mitsuru Shiraishi,2 Kenji Okonogi,2 and Masanori Baba1,*

Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890-8520,1 Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka 532-8686,2 Department of Microbiology, Kansai Medical University, Moriguchi 570-8506,3 and Discovery Research Division, Takeda Chemical Industries, Ltd., Osaka 532-8686,4 Japan

Received 2 April 2001/Returned for modification 12 July 2001/Accepted 27 August 2001

We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed beta -D-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC50s) for membrane fusion and viral replication were 0.87 ± 0.11 and 1.4 ± 0.1 nM, respectively. These values corresponded well to the IC50 for 125I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC50s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.

* Corresponding author. Mailing address: Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, 8-35-1, Sakuragaoka, Kagoshima 890-8520, Japan. Phone: 81-99-275-5930. Fax: 81-99-275-5932. E-mail: baba{at}m.kufm.kagoshima-u.ac.jp.

dagger Present address: Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.

Antimicrobial Agents and Chemotherapy, December 2001, p. 3538-3543, Vol. 45, No. 12
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.12.3538-3543.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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