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Journal of Virology, May 2003, p. 5201-5208, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5201-5208.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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,1 Francis Kajumo,1 Christoph Seibert,2 Shawn Kuhmann,3 Tom Ketas,3 Alexandra Trkola,4 Anadan Palani,5 John W. Clader,5 Jayaram R. Tagat,5 Stuart McCombie,5 Bahige Baroudy,5 John P. Moore,3 Thomas P. Sakmar,2 and Tatjana Dragic1*

Microbiology and Immunology Department, Albert Einstein College of Medicine, Bronx, New York 10461,1 Laboratory of Molecular Biology and Biochemistry, Howard Hughes Medical Institute, The Rockefeller University,2 Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021,3 Division of Infectious Diseases and Hospital Epidemiology, Department of Medicine, University of Zurich, Zurich 8091, Switzerland,4 Schering Plough Research Institute, Kenilworth, New Jersey 070335

Received 28 October 2002/ Accepted 3 January 2003

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.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. Phone: (718) 430-3282. Fax: (718) 430-8711. E-mail: tdragic{at}aecom.yu.edu.

Journal of Virology, May 2003, p. 5201-5208, Vol. 77, No. 9
0022-538X/03/$08.00+0     DOI: 10.1128/JVI.77.9.5201-5208.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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