title: Species selectivity of small-molecular antagonists for the CCR5 chemokine receptor.
abstract: The species selectivity of four structurally different compounds, SCH-351125, E-913, TAK-779 and UK-427857 has been examined using cloned human, rhesus, and mouse CCR5 receptors. SCH-351125 and E-913 potently inhibited the binding of [125I]-CCL3 to human CCR5, but their inhibitory activities against rhesus CCR5 were more than 10-fold weaker. In contrast, TAK-779 and UK-427857 inhibited binding to human and rhesus CCR5 with similar potency. The inhibitory activities of all four compounds against mice CCR5 receptors were weak. The inhibitory activities of the CCR5 antagonists in the [125I]-CCL3 binding assay agreed well with those induced by CCL3 in the intracellular calcium ([Ca(2+)]i) elevation assay. Mutational analysis of the human CCR5 receptor showed that its Ile198 component plays a critical role in the inhibitory activities of both SCH-351125 and E-913, but not that of TAK-779 or UK-427857. These results provide a structural basis for understanding how specific antagonists interact with CCR5, and will aid the process of creating new, improved CCR5 antagonists.
authors.affiliation: Molecular Medicine Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. yuuji.saita@jp.astellas.com
authors.forename: Yuji
authors.initials: Y
authors.lastname: Saita
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kondo
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D000577:Amides / Q000378:metabolism / Q000494:pharmacology; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001667:Binding, Competitive; D065100:CCR5 Receptor Antagonists; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D054405:Chemokine CCL3 / Q000378:metabolism / Q000494:pharmacology; D054407:Chemokine CCL4 / Q000378:metabolism; D018946:Chemokine CCL5 / Q000378:metabolism; D003497:Cyclic N-Oxides / Q000378:metabolism / Q000494:pharmacology; D003510:Cyclohexanes / Q000378:metabolism / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D008253:Macaca mulatta; D000077592:Maraviroc; D051379:Mice; D008969:Molecular Sequence Data; D010091:Oximes; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D014162:Transfection; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000577:Amides; D065100:CCR5 Receptor Antagonists; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018946:Chemokine CCL5; D003497:Cyclic N-Oxides; D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D010091:Oximes; D010880:Piperidines; D011725:Pyridines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D014230:Triazoles; C438583:Ancriviroc; C119369:TAK 779; D000077592:Maraviroc; D002118:Calcium