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Gene Review

CCR5  -  chemokine (C-C motif) receptor 5

Canis lupus familiaris

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Disease relevance of CCR5


High impact information on CCR5

  • Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry [5].
  • Here, we show that the chemokine receptor CCR5, a principal HIV-1 coreceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines [5].
  • We provide evidence that CCR5 is O-glycosylated on serine 6 in the NH2 terminus [3].
  • Three CCR5 mutants with little or no ability to mobilize calcium in response to macrophage inflammatory protein-1beta could nonetheless support HIV-1 entry and the early steps in the virus life cycle with efficiencies comparable with those of wild-type CCR5 [6].
  • These results identify a region of CCR5 that is necessary for the physical association of the gp120 envelope glycoprotein with CCR5 and for HIV-1 infection [7].

Chemical compound and disease context of CCR5

  • Maraviroc demonstrated potent antiviral activity against all CCR5-tropic HIV-1 viruses tested, including 43 primary isolates from various clades and diverse geographic origin (geometric mean 90% inhibitory concentration of 2.0 nM) [8].
  • Further optimization for pharmacokinetic properties afforded Sch-350634 (1), a prototypical piperazine-based CCR5 antagonist, which is a potent inhibitor of HIV-1 entry and replication in PBMCs [9].
  • Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist [9].
  • Compound (S)-(-)-5b (TAK-652) also inhibited the replication of six macrophage-tropic (CCR5-using or R5) HIV-1 clinical isolates in peripheral blood mononuclear cells (PBMCs) (mean IC90=0.25 nM) [10].

Biological context of CCR5

  • The deduced amino acid sequence of the dog CCR5 has close homology to the human receptor (80% identity) [1].
  • In a CRE-Luc (cAMP response element-luciferase) reporter gene assay, MIP-1beta (0.01-30nM) produced concentration-dependent inhibition of forskolin induced elevation in cAMP levels, and was equipotent in dog, human and macaque recombinant CCR5 cells (EC(50) 0.4, 0.21 and 0.47nM, respectively) [1].
  • The dog CCR5 gene was cloned in order to characterise the chemokine binding site of the dog receptor for comparison across species [1].
  • The mechanism of action of maraviroc was established using cell-based assays, where it blocked binding of viral envelope, gp120, to CCR5 to prevent the membrane fusion events necessary for viral entry [8].

Anatomical context of CCR5

  • Activation of CCR5 by specific chemokines is involved in the regulation of the immunological response of leukocytes at sites of inflammation [1].
  • A HEK-293 cell line expressing the dog recombinant receptor was generated and immunoblot analysis with an anti-human CCR5 antibody revealed a 58kDa band in the cell lysate [1].
  • Both complement receptor (CD35) and Fc gamma receptor (CD64) were demonstrated on the cell membrane [11].

Associations of CCR5 with chemical compounds

  • Maraviroc is the product of a medicinal chemistry effort initiated following identification of an imidazopyridine CCR5 ligand from a high-throughput screen of the Pfizer compound file [8].
  • Chemical modification has been performed on an orally bioavailable and potent CCR5 antagonist, sulfoxide compound 4, mainly focusing on replacement of the [6,7]-fused 1-benzazepine nucleus [10].
  • Introduction of small hydrophobic substituents on the central phenyl ring increased the binding affinity, providing low to sub-nanomolar CCR5 antagonists [12].
  • Thus, as has been observed for the binding of selectins and their ligands, O-linked carbohydrates and tyrosine sulfates play major roles in promoting the interaction of chemokines with CCR5 [3].

Analytical, diagnostic and therapeutic context of CCR5


  1. The molecular cloning and functional expression of the dog CCR5. Mosley, M., Pullen, S., Botham, A., Gray, A., Napier, C., Mansfield, R., Holbrook, M. Vet. Immunol. Immunopathol. (2006) [Pubmed]
  2. Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV. Walker, D.K., Abel, S., Comby, P., Muirhead, G.J., Nedderman, A.N., Smith, D.A. Drug Metab. Dispos. (2005) [Pubmed]
  3. Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines. Bannert, N., Craig, S., Farzan, M., Sogah, D., Santo, N.V., Choe, H., Sodroski, J. J. Exp. Med. (2001) [Pubmed]
  4. Expression and utilization of co-receptors in HIV and simian immunodeficiency virus infection of megakaryocytes. Park, I.W., Wang, J.F., Groopman, J.E. AIDS (1999) [Pubmed]
  5. Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. Farzan, M., Mirzabekov, T., Kolchinsky, P., Wyatt, R., Cayabyab, M., Gerard, N.P., Gerard, C., Sodroski, J., Choe, H. Cell (1999) [Pubmed]
  6. HIV-1 entry and macrophage inflammatory protein-1beta-mediated signaling are independent functions of the chemokine receptor CCR5. Farzan, M., Choe, H., Martin, K.A., Sun, Y., Sidelko, M., Mackay, C.R., Gerard, N.P., Sodroski, J., Gerard, C. J. Biol. Chem. (1997) [Pubmed]
  7. A tyrosine-rich region in the N terminus of CCR5 is important for human immunodeficiency virus type 1 entry and mediates an association between gp120 and CCR5. Farzan, M., Choe, H., Vaca, L., Martin, K., Sun, Y., Desjardins, E., Ruffing, N., Wu, L., Wyatt, R., Gerard, N., Gerard, C., Sodroski, J. J. Virol. (1998) [Pubmed]
  8. Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Dorr, P., Westby, M., Dobbs, S., Griffin, P., Irvine, B., Macartney, M., Mori, J., Rickett, G., Smith-Burchnell, C., Napier, C., Webster, R., Armour, D., Price, D., Stammen, B., Wood, A., Perros, M. Antimicrob. Agents Chemother. (2005) [Pubmed]
  9. Piperazine-based CCR5 antagonists as HIV-1 inhibitors. II. Discovery of 1-[(2,4-dimethyl-3-pyridinyl)carbonyl]-4- methyl-4-[3(S)-methyl-4-[1(S)-[4-(trifluoromethyl)phenyl]ethyl]-1-piperazinyl]- piperidine N1-oxide (Sch-350634), an orally bioavailable, potent CCR5 antagonist. Tagat, J.R., Steensma, R.W., McCombie, S.W., Nazareno, D.V., Lin, S.I., Neustadt, B.R., Cox, K., Xu, S., Wojcik, L., Murray, M.G., Vantuno, N., Baroudy, B.M., Strizki, J.M. J. Med. Chem. (2001) [Pubmed]
  10. Highly potent and orally active CCR5 antagonists as anti-HIV-1 agents: synthesis and biological activities of 1-benzazocine derivatives containing a sulfoxide moiety. Seto, M., Aikawa, K., Miyamoto, N., Aramaki, Y., Kanzaki, N., Takashima, K., Kuze, Y., Iizawa, Y., Baba, M., Shiraishi, M. J. Med. Chem. (2006) [Pubmed]
  11. Establishment of a canine monocyte cell line. Kadoi, K. New Microbiol. (2000) [Pubmed]
  12. CCR5 antagonists as anti-HIV-1 agents. Part 3: Synthesis and biological evaluation of piperidine-4-carboxamide derivatives. Imamura, S., Nishikawa, Y., Ichikawa, T., Hattori, T., Matsushita, Y., Hashiguchi, S., Kanzaki, N., Iizawa, Y., Baba, M., Sugihara, Y. Bioorg. Med. Chem. (2005) [Pubmed]
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