1st International Workshop on HIV Drug Resistance & Treatment Strategies 25-28 June 1997, St. Petersburg, Florida, USA

THE BICYCLAM AMD3100, A POTENT INHIBITOR OF T-TROPIC HIV STRAINS, IS TARGETED AT THE HIV CO-RECEPTOR CXCR4

Antiviral Therapy 1997;2 (Suppl 5):2 (abstract no. 3)

Dominique Schols¹, José A Esté¹, Geoffrey Henson² and Erik De Clercq^1
1Rega Institute for Medical Research, B-3000 Leuven, Belgium; and ²AnorMED, Langley, British Columbia, Canada

Bicyclams are a novel class of antiviral compounds which are highly potent and selective inhibitors of the replication of HIV-1 and HIV-2. The prototype compound, AMD3100, has an IC₅₀ of 1-10 nM, which is a least 100,000-fold lower than the cytotoxic concentration. AMD3100 does not inhibit virus binding to the CD4 receptor and, based on time-of-addition experiments, has been assumed to interact with the HIV fusion-uncoating process. Resistance of HIV-1 strains to AMD3100 is associated with the accumulation of several mutations in the viral envelope glycoprotein gp120. Here, we demonstrate that AMD3100 specifically interacts with fusin, recently called CXCR4, the co-receptor used by T-tropic viruses to infect their target cells. AMD3100, at 1 µg/ml, completely inhibited the binding of the 12G5 MAb to CXCR-4 on T cells. AMD3100 was not active against the M-tropic viruses BaL, ADA, JR-CSF and SF-162, and the simian immunodeficiency virus strain MAC251 in human T cells. These viruses use CCR5 (or other CCRs, but not CXCR4) to enter T cells. The replication of the T-tropic bicyclam-sensitive NL4-3 wild-type virus and NL4-3 dextran sulphate-resistant virus was inhibited by the CXC chemokine, SDF-1α (IC₅₀ 0.1 µg/ml), the natural ligand for CXCR4, whereas the replication of the bicyclam-resistant HIV-1 NL4-3 virus was no longer inhibited by SDF-1α (IC₅₀ >2 µg/ml). In conclusion, the bicyclams are the first low molecular weight anti-HIV agents found to interact specifically with CXCR4, the co-receptor for HIV. AMD3100 holds great promise as a candidate anti-HIV drug and clinical trials with the compound are planned.

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1997-06-25
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