CCR5

Models also can assist in experimental design and the determination of the limits of experimental systems. For example, it is known that three proteins mediate the interaction of HIV with cells namely, the chemokine receptor CCR5, the cellular protein CD4, and the viral coat protein gpl20. An extremely useful experimental system to study this interaction is one in which radioactive CD4, prebound to soluble gpl20, is allowed to bind to cellular receptor CCR5. This system can be used to screen for... 

FIGURE 3.12 Dependence of constitutive receptor activity as ordinates (expressed as a percent of the maximal response to a full agonist for each receptor) versus magnitude of receptor expression (expressed as the amount of human cDNA used for transient transfection, logarithmic scale) in Xenopus laevis melanophores. Data shown for human chemokine CCR5 receptors (open circles), chemokine CXCR receptors (filled triangles), neuropeptide Y type 1 receptors (filled diamonds), neuropeptide Y type 2 receptors (open squares), and neuropeptide Y type 4 receptors (open inverted triangles). Data recalculated and redrawn from [27],... 

Assuming that all interactions of the species are possible, the system consists of the receptor CCR5 [R], radioligand CD4 [CD]), viral coat protein gpl20 [gp], and potential displacing ligand [B] ... 

FIGURE 7.3 Diversity of structures that interact with the (a) HIV reverse transcriptase inhibitor binding site [8] and (b) the CCR5 receptor mediating HIV-1 fusion [9],... 

Watson, C., Jenkinson, S., Kazmierski,W., and Kenakin, T. P. (2005). The CCR5 receptor-based mechanism of action of 873140, a potent allosteric non-competitive HIV entry-inhibitor. Mol. Pharmacol. 67 1268—1282. 

M. A., Dorns, R. W., and Peiper, S. C. (1997). Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1. J. Virol. 71 6305-6314. 

J., Palani, A., Shapiro, S., Clader, J. W., McCombie, S., Reyes, G. R., Baroudy, B. M., and Moore, J. P. (2002). HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use. Proc. Natl. Acad. Sci. USA 99 395-100. 

Finke, P. E., Oates, B., Mills, S. G., MacCoss, M., Malkowitz, L., Springer, M. S., Gould, S. L., DeMartino, J. A., Carella, A. Carver, G., et al. (2001). Antagonists of the human CCR5 receptor as anti-HIV-1 agents. Part 4 synthesis and structure—Activity relationships for l-[7V-(Methyl)-7V-(phenylsulfonyl)amino]-2-(phenyl)-4-(4-(7V-(alkyl)-7V-(benzylox-ycarbonyl)amino)piperidin-l-yl)butanes. Bioorg. Med. Chem. Lett. 11 2475-2479. 

CCR2 plus CCR5 6-opioid plus K-opioid... 

Zaitseva, M., Blauvelt, A., Lee, S., Lapham, C. K., Klaus-Kovtun, V., Mostowski, H., Manischewitz, J., and Golding, H. (1997). Expression and function of CCR5 and CXCR4 on human langerhans cells and macrophages Implications for HIV primary infection. Nature Medicine 3 1369-1375. 

A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. AcadSci. USA 96 5698-5703. 

CCR5 receptors, 177 high-throughput screening of drugs for,... 

---