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

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 (IC(50)s) 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 (IC(50), 62 ng/ml) than in CRFK cells (IC(50), 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 (IC(50), >66.5 μg/ml), while it was clearly active in CRFK cells (IC(50), 0.9 μg/ml). The CXC chemokine stromal-cell-derived factor 1α had anti-FIV activity in CRFK cells (IC(50), 200 ng/ml) but not in feline thymocytes (IC(50), >2.5 μg/ml). When primary FIV isolates were evaluated for their drug susceptibility in feline thymocytes, the bicyclams AMD3100 and its Zn(2+) 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.