Disease relevance of CCR5

• Consequently, several CCR5 antagonists are currently in development for the treatment of HIV-1 infection [1].
• Species differences in the disposition of the CCR5 antagonist, UK-427,857, a new potential treatment for HIV [2].
• The chemokine receptor CCR5 plays an important role in leukocyte chemotaxis and activation, and also acts as a coreceptor for human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) [3].
• 9. RESULTS: The model human erythroleukemia (HEL) cell line, exhibiting megakaryocytic-like properties, expressed CCR5, CCR3, CXCR4, and CPR15/BOB, and all viruses except YU2 (R5) efficiently entered the cells [4].

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

• The molecular cloning and functional expression of the dog CCR5 [1].

References