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Journal of Virology, August 1999, p. 6346-6352, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Bicyclams, Selective Antagonists of the Human Chemokine Receptor CXCR4, Potently Inhibit Feline Immunodeficiency Virus Replication

Herman F. Egberink,1 Erik De Clercq,2 Arno L. W. Van Vliet,1 Jan Balzarini,2 Gary J. Bridger,3 Geoffrey Henson,3 Marian C. Horzinek,1 and Dominique Schols2,*

Institute of Virology, Utrecht University, 3584 CL Utrecht, The Netherlands1; Rega Institute for Medical Research, Katholicke Universiteit Leuven, B-3000 Leuven, Belgium2; and AnorMED Inc., Langley, British Columbia V2Y 1N5, Canada3

Received 11 January 1999/Accepted 4 May 1999

Bicyclams are low-molecular-weight anti-human immunodeficiency virus (HIV) agents that have been shown to act as potent and selective CXC chemokine receptor 4 (CXCR4) antagonists. Here, we demonstrate that bicyclams are potent inhibitors of feline immunodeficiency virus (FIV) replication when evaluated in Crandell feline kidney (CRFK) cells. With a series of bicyclam derivatives, 50% inhibitory concentrations (IC50s) against FIV were obtained in this cell system that were comparable to those obtained for HIV-1 IIIB replication in the human CD4+ MT-4 T-cell line. The bicyclams were also able to block FIV replication in feline thymocytes, albeit at higher concentrations than in the CRFK cells. The prototype bicyclam AMD3100, 1-1'-[1,4-phenylene-bis(methylene)]-bis(1,4,8,11-tetraazacyclotetradecane), was only fourfold less active in feline thymocytes (IC50, 62 ng/ml) than in CRFK cells (IC50, 14 ng/ml). AMD2763, 1,1'-propylene-bis(1,4,8,11-tetraazacyclotetradecane), which is a less potent CXCR4 antagonist, was virtually inactive against FIV in feline thymocytes (IC50, >66.5 µg/ml), while it was clearly active in CRFK cells (IC50, 0.9 µg/ml). The CXC chemokine stromal-cell-derived factor 1alpha had anti-FIV activity in CRFK cells (IC50, 200 ng/ml) but not in feline thymocytes (IC50, >2.5 µg/ml). When primary FIV isolates were evaluated for their drug susceptibility in feline thymocytes, the bicyclams AMD3100 and its Zn2+ complex, AMD3479, inhibited all six primary isolates at equal potency. The marked susceptibility of FIV to the bicyclams suggests that FIV predominantly uses feline CXCR4 for entering its target cells.

* Corresponding author. Mailing address: Rega Institute for Medical Research, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Phone: 32-16-33.73.41. Fax: 32-16-33.73.40. E-mail: dominique.schols{at}rega.kuleuven.ac.be.

Journal of Virology, August 1999, p. 6346-6352, Vol. 73, No. 8
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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