AMD3100 is a failed anti-HIV treatment which belongs to the new class of drugs known as CXCR4 inhibitors. This class of drug stops the process of HIV attachment and entry into CD4 T-cells through blocking the use of the CXCR4 co-receptor. AMD3100 belongs to a sub-category of fusion inhibitors called bicyclams, which are made up of two cyclam rings. AMD3100, sometimes referred to as JM3100, was the leading drug in this class.

AMD3100 inhibits virus which uses the CXCR4 receptor, the receptor used by syncytium-inducing phenotype of HIV. This HIV variant is associated with a fast CD4 T-cell decline and late-stage HIV disease. AMD3100 is not active against the more common variant which uses the CCR5 co-receptor. CXCR4 is expressed on a much wider range of cell types than CCR5, and the potential for adverse effects from CXCR4 inhibition may thus be greater.

Development of AMD3100 was abandoned in May 2001 due to possible cardiac toxicity and limited efficacy. Administration by intravenous infusion or subcutaneous injection in HIV-negative individuals achieved concentrations greater than the in vitro IC₉₀ for HIV-1 for 12 and 8 hours, respectively, but the results of preliminary studies in HIV-infected patients were unimpressive (Datema 1996; Hendrix 2000, 2004).

Preliminary evidence of resistance to AMD3100 was also discouraging. Test-tube data showed that mutations in the CXCR4 co-receptor at codons 171 and 262 rendered AMD3100 ineffective against HIV. Interestingly, these mutations also interfered with the ability of HIV to use CXCR4 as a co-receptor, and may be associated with a slowing of disease progression by forcing the virus to use the CCR5 co-receptor (Hatse 2001; Huang 2004).

References

Blanco J et al. The CXCR4 antagonist AMD3100 efficiently inhibits cell-surface-expressed human immunodeficiency virus type 1 envelope-induced apoptosis. Antimicrobial Agents and Chemotherapy 44(1): 51-56, 2000.

Datema R et al. Antiviral efficacy in vivo of the anti-human immunodeficiency virus bicyclam SDZ SID 791 (JM 3100), an inhibitor of infectious cell entry. Antimicrobial Agents and Chemotherapy 40: 750-754, 1996.

Hatse S et al. Mutation of Asp (171) and Asp(262) of the chemokine receptor CXCR4 impairs its coreceptor function for human immunodeficiency virus-1 entry and abrogates the antagonistic activity of AMD3100. Mol Pharmacol 60(1):164-173, 2001.

Hendrix CW et al. Pharmacokinetics and safety of AMD-3100, a novel antagonist of the CXCR-4 chemokine receptor, in human volunteers. Antimicrobial Agents and Chemotherapy 44: 1667-1673, 2000.

Hendrix CW et al. Pharmacokinetics, and antiviral activity of AMD3100, a selective CXCR4 receptor inhibitor, in HIV-1 infection. J Acquir Immune Defic Syndr 37: 1253-1262, 2004.

Huang W et al. Suppression of X4- and dula-tropic HIV-1 variants during a short course of monotherapy with the CXCR4 antagonist AMD3100. Thirteenth International HIV Drug Resistance Workshop, Costa Adeje, abstract 7, 2004.

Tremblay C et al. Strong in vitro synergy observed between the fusion inhibitor T-20 and a CXCR4 blocker AMD-3100C. Seventh Conference on Retroviruses and Opportunistic Infections, San Francisco, abstract 500, 2000.