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Antimicrobial Agents and Chemotherapy, November 2005, p. 4708-4715, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4708-4715.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Analysis of Binding Sites for the New Small-Molecule CCR5 Antagonist TAK-220 on Human CCR5

Masao Nishikawa,1 Katsunori Takashima,2 Toshiya Nishi,2 Rika A. Furuta,1 Naoyuki Kanzaki,2 Yoshio Yamamoto,2 and Jun-ichi Fujisawa1*

Department of Microbiology, Kansai Medical University, Osaka 570-8506,1 Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., Osaka 532-8686, Japan2

Received 19 March 2005/ Returned for modification 10 May 2005/ Accepted 26 August 2005

G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.

* Corresponding author. Mailing address: Department of Microbiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan. Phone: 81-6-6993-9433. Fax: 81-6-6993-1668. E-mail: fujisawa{at}takii.kmu.ac.jp.

Antimicrobial Agents and Chemotherapy, November 2005, p. 4708-4715, Vol. 49, No. 11
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.11.4708-4715.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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