Received for publication October 21, 2004.
Revised January 9, 2005.
Accepted for publication January 10, 2005.

The CCR5 Receptor-based mechanism of action of 873140, a potent allosteric non-competitive HIV entry-inhibitor

Abstract

873140 is a potent non-competitive allosteric antagonist of the CCR5 receptor (pK_B =8.6 ± 0.07 ; 95 % c.l. = 8.5 to 8.8) with concomitantly potent antiviral effects for HIV-1. In this paper, the receptor-based mechanism of action of 873140 is compared to four other non-competitive allosteric antagonists of CCR5. While Sch-C, Sch-D, UK-427,857, and TAK779 blocked both the binding of the chemokines ¹²⁵I-MIP-1 (also known as ¹²⁵I-CCL3, ¹²⁵I-LD78) and ¹²⁵IRANTES (¹²⁵I-CCL5), 873140 was an ineffectual antagonist of ¹²⁵I-RANTES binding (but did block binding of ¹²⁵I-MIP-1 ). Furthermore, 873140 blocked the calcium response effects of CCR5 activation by CCL5 (RANTES) (as did the other antagonists) indicating a unique divergence of blockade of function and binding with this antagonist. The antagonism of CCR5 by 873140 is saturable and probe dependent consistent with an allosteric mechanism of action. The blockade of CCR5 by 873140 was extremely persistent with a rate constant for reversal of <0.004 h^-1 (t _1/2 > 136h). Co-administration studies of 873140 with the four other allosteric antagonists yielded data that is consistent with the notion that all five of these antagonists bind to a common allosteric site on the CCR5 receptor. While these ligands may have a common binding site, they do not exert the same allosteric effect on the receptor as indicated by their differential effects on the binding of 125I-RANTES. This idea is discussed in terms of using these drugs sequentially to overcome HIV viral resistance in the clinic.

Key words: Chemotactic peptides, Prediction of structure-function/proteomics, Antiviral drugs

This article has been cited by other articles:

				V. Musante, F. Longordo, E. Neri, M. Pedrazzi, F. Kalfas, P. Severi, M. Raiteri, and A. Pittaluga RANTES Modulates the Release of Glutamate in Human Neocortex J. Neurosci., November 19, 2008; 28(47): 12231 - 12240. [Abstract] [Full Text] [PDF]

				J. F. Demarest, S. S. Sparks, K. Schell, S. Shibayama, C. B. McDanal, L. Fang, K. K. Adkison, A. Shachoy-Clark, and S. C. Piscitelli In Vitro and Clinical Investigation of the Relationship Between CCR5 Receptor Occupancy and Anti-HIV Activity of Aplaviroc J. Clin. Pharmacol., October 1, 2008; 48(10): 1179 - 1188. [Abstract] [Full Text] [PDF]

				T. P. Kenakin Seven Transmembrane Receptors as Nature's Prototype Allosteric Protein: De-emphasizing the Geography of Binding Mol. Pharmacol., September 1, 2008; 74(3): 541 - 543. [Abstract] [Full Text] [PDF]

				A. M. N. Tsibris, M. Sagar, R. M. Gulick, Z. Su, M. Hughes, W. Greaves, M. Subramanian, C. Flexner, F. Giguel, K. E. Leopold, et al. In Vivo Emergence of Vicriviroc Resistance in a Human Immunodeficiency Virus Type 1 Subtype C-Infected Subject J. Virol., August 15, 2008; 82(16): 8210 - 8214. [Abstract] [Full Text] [PDF]

				R. Kondru, J. Zhang, C. Ji, T. Mirzadegan, D. Rotstein, S. Sankuratri, and M. Dioszegi Molecular Interactions of CCR5 with Major Classes of Small-Molecule Anti-HIV CCR5 Antagonists Mol. Pharmacol., March 1, 2008; 73(3): 789 - 800. [Abstract] [Full Text] [PDF]

				K. M. Nolan, A. P. O. Jordan, and J. A. Hoxie Effects of Partial Deletions within the Human Immunodeficiency Virus Type 1 V3 Loop on Coreceptor Tropism and Sensitivity to Entry Inhibitors J. Virol., January 15, 2008; 82(2): 664 - 673. [Abstract] [Full Text] [PDF]

				G. Lin, A. Bertolotti-Ciarlet, B. Haggarty, J. Romano, K. M. Nolan, G. J. Leslie, A. P.-O. Jordan, C.-c. Huang, P. D. Kwong, R. W. Doms, et al. Replication-Competent Variants of Human Immunodeficiency Virus Type 2 Lacking the V3 Loop Exhibit Resistance to Chemokine Receptor Antagonists J. Virol., September 15, 2007; 81(18): 9956 - 9966. [Abstract] [Full Text] [PDF]

				W. Gonsiorek, X. Fan, D. Hesk, J. Fossetta, H. Qiu, J. Jakway, M. Billah, M. Dwyer, J. Chao, G. Deno, et al. Pharmacological Characterization of Sch527123, a Potent Allosteric CXCR1/CXCR2 Antagonist J. Pharmacol. Exp. Ther., August 1, 2007; 322(2): 477 - 485. [Abstract] [Full Text] [PDF]

				P. C. Jensen, R. Nygaard, S. Thiele, A. Elder, G. Zhu, R. Kolbeck, S. Ghosh, T. W. Schwartz, and M. M. Rosenkilde Molecular Interaction of a Potent Nonpeptide Agonist with the Chemokine Receptor CCR8 Mol. Pharmacol., August 1, 2007; 72(2): 327 - 340. [Abstract] [Full Text] [PDF]

				C. Ji, J. Zhang, M. Dioszegi, S. Chiu, E. Rao, A. deRosier, N. Cammack, M. Brandt, and S. Sankuratri CCR5 Small-Molecule Antagonists and Monoclonal Antibodies Exert Potent Synergistic Antiviral Effects by Cobinding to the Receptor Mol. Pharmacol., July 1, 2007; 72(1): 18 - 28. [Abstract] [Full Text] [PDF]

				J. Zhang, E. Rao, M. Dioszegi, R. Kondru, A. DeRosier, E. Chan, S. Schwoerer, N. Cammack, M. Brandt, S. Sankuratri, et al. The Second Extracellular Loop of CCR5 Contains the Dominant Epitopes for Highly Potent Anti-Human Immunodeficiency Virus Monoclonal Antibodies Antimicrob. Agents Chemother., April 1, 2007; 51(4): 1386 - 1397. [Abstract] [Full Text] [PDF]

				G. Gaibelet, T. Planchenault, S. Mazeres, F. Dumas, F. Arenzana-Seisdedos, A. Lopez, B. Lagane, and F. Bachelerie CD4 and CCR5 Constitutively Interact at the Plasma Membrane of Living Cells: A CONFOCAL FLUORESCENCE RESONANCE ENERGY TRANSFER-BASED APPROACH J. Biol. Chem., December 8, 2006; 281(49): 37921 - 37929. [Abstract] [Full Text] [PDF]

				T. Kenakin, S. Jenkinson, and C. Watson Determining the Potency and Molecular Mechanism of Action of Insurmountable Antagonists J. Pharmacol. Exp. Ther., November 1, 2006; 319(2): 710 - 723. [Abstract] [Full Text] [PDF]

				J. D. Murga, M. Franti, D. C. Pevear, P. J. Maddon, and W. C. Olson Potent Antiviral Synergy between Monoclonal Antibody and Small-Molecule CCR5 Inhibitors of Human Immunodeficiency Virus Type 1. Antimicrob. Agents Chemother., October 1, 2006; 50(10): 3289 - 3296. [Abstract] [Full Text] [PDF]

				E. Chan, G. Heilek-Snyder, N. Cammack, S. Sankuratri, and C. Ji Development of a Moloney Murine Leukemia Virus-Based Pseudotype Anti-HIV Assay Suitable for Accurate and Rapid Evaluation of HIV Entry Inhibitors J Biomol Screen, September 1, 2006; 11(6): 652 - 663. [Abstract] [PDF]

				M. M. Lederman, A. Penn-Nicholson, M. Cho, and D. Mosier Biology of CCR5 and its role in HIV infection and treatment. JAMA, August 16, 2006; 296(7): 815 - 826. [Abstract] [Full Text] [PDF]

				B. M. Johnson, I. H. Song, K. K. Adkison, J. Borland, L. Fang, Y. Lou, M. M. Berrey, A. N. Nafziger, S. C. Piscitelli, and J. S. Bertino Jr Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail. J. Clin. Pharmacol., May 1, 2006; 46(5): 577 - 587. [Abstract] [Full Text] [PDF]

				C. Ji, J. Zhang, N. Cammack, and S. Sankuratri Development of a Novel Dual CCR5-Dependent and CXCR4-Dependent Cell-Cell Fusion Assay System with Inducible gp160 Expression J Biomol Screen, February 1, 2006; 11(1): 65 - 74. [Abstract] [PDF]

				P. Dorr, M. Westby, S. Dobbs, P. Griffin, B. Irvine, M. Macartney, J. Mori, G. Rickett, C. Smith-Burchnell, C. Napier, et al. 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 Antimicrob. Agents Chemother., November 1, 2005; 49(11): 4721 - 4732. [Abstract] [Full Text] [PDF]

				M. R. Price, G. L. Baillie, A. Thomas, L. A. Stevenson, M. Easson, R. Goodwin, A. McLean, L. McIntosh, G. Goodwin, G. Walker, et al. Allosteric Modulation of the Cannabinoid CB1 Receptor Mol. Pharmacol., November 1, 2005; 68(5): 1484 - 1495. [Abstract] [Full Text] [PDF]