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* Molecular Medicine Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan;
Laboratory of Virus Immunology, Research Center for AIDS, Institute for Virus Research, Kyoto University, Kyoto, Japan;
Lead Discovery Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan; and
Pharmacology Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Osaka, Japan
The chemokine receptor CCR5 is an attractive target for HIV-1 drug development, as individuals whose cells lack surface CCR5 expression are highly resistant to HIV-1 infection. CCR5 ligands, such as CCL5/RANTES, effectively inhibit HIV-1 infection by competing for binding opportunities to the CCR5 and inducing its internalization. However, the inherent proinflammatory activity of the chemotactic response of CCR5 ligands has limited their clinical use. In this study, we found that a novel small molecule, functionally selective CCR5 agonist, 2,2-dichloro-1-(triphenylphosphonio)vinyl formamide perchlorate (YM-370749), down-modulates CCR5 from the cell surface without inducing a chemotactic response and inhibits HIV-1 replication. In molecular docking studies of YM-370749 and a three-dimensional model of CCR5 based on the rhodopsin crystal structure as well as binding and functional studies using various CCR5 mutants, the amino acid residues necessary for interaction with YM-370749 were marked. These results provide a structural basis for understanding the activation mechanism of CCR5 and for designing functionally selective agonists as a novel class of anti-HIV-1 agents.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Yuji Saita, Molecular Medicine Research Laboratories, Institute for Drug Discovery Research, Astellas Pharama Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. E-mail address: yuuji.saita{at}jp.astellas.com
2 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; B300-19/CCR5, B300-19 cells expressing CCR5; 
Gal, -galactosidase; [Ca2+]i, intracellular Ca2+ concentration; EGFP, enhanced GFP; FluV-A, influenza virus type A; GPCR, G protein-coupled receptor; LTR, long-terminal repeat; PHAM, PHA M; TM, transmembrane; YM-370749, 2,2-dichloro-1-(triphenylphosphonio)vinyl formamide perchlorate; WT, wild type.
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