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. 2003 May;77(9):5201-8.
doi: 10.1128/jvi.77.9.5201-5208.2003.

Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry

Fotini Tsamis  1 , Svetlana Gavrilov, Francis Kajumo, Christoph Seibert, Shawn Kuhmann, Tom Ketas, Alexandra Trkola, Anadan Palani, John W Clader, Jayaram R Tagat, Stuart McCombie, Bahige Baroudy, John P Moore, Thomas P Sakmar, Tatjana Dragic
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Analysis of the mechanism by which the small-molecule CCR5 antagonists SCH-351125 and SCH-350581 inhibit human immunodeficiency virus type 1 entry

Fotini Tsamis et al. J Virol. 2003 May.

Abstract

Human immunodeficiency virus type 1 (HIV-1) entry is mediated by the consecutive interaction of the envelope glycoprotein gp120 with CD4 and a coreceptor such as CCR5 or CXCR4. The CCR5 coreceptor is used by the most commonly transmitted HIV-1 strains that often persist throughout the course of infection. Compounds targeting CCR5-mediated entry are a novel class of drugs being developed to treat HIV-1 infection. In this study, we have identified the mechanism of action of two inhibitors of CCR5 function, SCH-350581 (AD101) and SCH-351125 (SCH-C). AD101 is more potent than SCH-C at inhibiting HIV-1 replication in primary lymphocytes, as well as viral entry and gp120 binding to cell lines. Both molecules also block the binding of several anti-CCR5 monoclonal antibodies that recognize epitopes in the second extracellular loop of CCR5. Alanine mutagenesis of the transmembrane domain of CCR5 suggests that AD101 and SCH-C bind to overlapping but nonidentical sites within a putative ligand-binding cavity formed by transmembrane helices 1, 2, 3, and 7. We propose that the binding of small molecules to the transmembrane domain of CCR5 may disrupt the conformation of its extracellular domain, thereby inhibiting ligand binding to CCR5.

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Figures

FIG. 1.
FIG. 1.
Inhibition of viral replication and entry by AD101 and SCH-C. (a) Replication of HIV-1JR-FL was measured in mitogen-stimulated human PBMC in the presence of different concentrations of AD101 (black squares) or SCH-C (white circles). The perccent HIV-1JR-FL replication is defined as (nanograms of p24 with inhibitor/nanograms of p24 without inhibitor) × 100% and is plotted as a function of AD101 or SCH-C concentration. (b) Entry of HIV-1JR-FL Env-pseudotyped reporter viruses into U87-CD4 cells transiently expressing the CCR5 coreceptor was measured in the presence of different concentrations of AD101 (black squares) or SCH-C (white circles). The percent viral entry is defined as (RLU with inhibitor/RLU without inhibitor) × 100% and is plotted as a function of AD101 or SCH-C concentration. All values are means ± SD of three independent experiments.
FIG. 2.
FIG. 2.
Inhibition of gp120 and MAb binding by AD101 and SCH-C. (a) Binding of gp120JR-FL-CD4-IgG2 to L1.2 cells expressing the CCR5 coreceptor was measured in the presence of different concentrations of AD101 (black squares) or SCH-C (white circles). The percent inhibition of gp120-CCR5 binding is defined as (MFI with inhibitor/MFI without inhibitor) × 100% and is plotted as a function of AD101 or SCH-C concentration. (b) Alternatively, binding of anti-CCR5 MAbs to L1.2 cells was measured in the presence of 100 nM AD101 (gray bars) or SCH-C (white bars). The percent inhibition of MAb binding is defined as (MFI with inhibitor/MFI without inhibitor) × 100%. All values are means ± SD of three independent experiments.
FIG. 3.
FIG. 3.
Residues important for AD101 and SCH-C activity. A two-dimensional model of CCR5 depicts the extracellular loops, the seven TM helices, and the intracellular loops of the coreceptor. Residues important for binding of AD101 and SCH-C are in black; residues important only for AD101 binding are in gray. Residues thought to exert indirect effects on the activities of the inhibitors are circled in bold.
FIG. 4.
FIG. 4.
Model of the mechanism of action of small-molecule inhibitors of CCR5 coreceptor function. gp120 is initially in a closed state, wherein the V1/V2 and V3 loops conceal the coreceptor binding site. Upon CD4 binding to gp120, conformational changes create and/or expose the coreceptor binding site. In the absence of inhibitor, the CCR5 Nt interacts with residues in the bridging sheet (BS) and the V3 stem, whereas ECL2 interacts with the V3 crown. In the presence of inhibitor, the conformation of ECL2 is modified such that it can no longer interact with the V3 crown, thus inhibiting viral entry.
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References

    1. Baba, M., O. Nishimura, N. Kanzaki, M. Okamoto, H. Sawada, Y. Iizawa, M. Shiraishi, Y. Aramaki, K. Okonogi, Y. Ogawa, K. Meguro, and M. Fujino. 1999. A small-molecule, nonpeptide CCR5 antagonist with highly potent and selective anti-HIV-1 activity. Proc. Natl. Acad. Sci. USA 96:5698-5703. - PMC - PubMed
    1. Berger, E. A., P. M. Murphy, and J. M. Farber. 1999. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease. Annu. Rev. Immunol. 17:657-700. - PubMed
    1. Cocchi, F., A. L. DeVico, A. Garzino-Demo, S. K. Arya, R. C. Gallo, and P. Lusso. 1995. Identification of RANTES, MIP-1 alpha, and MIP-1 beta as the major HIV-suppressive factors produced by CD8+ T cells. Science 270:1811-1815. - PubMed
    1. Cormier, E. G., D. N. Tran, L. Yukhayeva, W. C. Olson, and T. Dragic. 2001. Mapping the determinants of the CCR5 amino-terminal sulfopeptide interaction with soluble human immunodeficiency virus type 1 gp120-CD4 complexes. J. Virol. 75:5541-5549. - PMC - PubMed
    1. Dealwis, C., E. J. Fernandez, D. A. Thompson, R. J. Simon, M. A. Siani, and E. Lolis. 1998. Crystal structure of chemically synthesized [N33A] stromal cell-derived factor 1α, a potent ligand for the HIV-1 “fusin” coreceptor. Proc. Natl. Acad. Sci. USA 95:6941-6946. - PMC - PubMed

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