Highly potent and selective inhibition of human immunodeficiency virus by the bicyclam derivative JM3100

Abstract

Bicyclams, in which the cyclam (1,4,8,11-tetraazacyclotetradecane) moieties are tethered via an aliphatic bridge (i.e., propylene, as in JM2763) are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) (E. De Clercq, N. Yamamoto, R. Pauwels, M. Baba, D. Schols, H. Nakashima, J. Balzarini, Z. Debyser, B. A. Murrer, D. Schwartz, D. Thornton, G. Bridger, S. Fricker, G. Henson, M. Abrams, and D. Picker, Proc. Natl. Acad. Sci. USA 89:5286-5290, 1992). We have now found that the bicyclam JM3100, in which the cyclam moieties are tethered by an aromatic bridge [i.e., phenylenebis(methylene)], inhibits the replication of various HIV-1 and HIV-2 strains in various cell lines at a 50% effective concentration (EC50) of 1 to 10 ng/ml, which is about 100-fold lower than the concentration required for JM2763 to inhibit HIV replication and at least 100,000-fold lower than the cytotoxic concentration (> 500 micrograms/ml). In primary T4 lymphocytes or primary monocytes, JM3100 proved inhibitory to HIV-1(IIIB) and several clinical HIV-1 isolates at an EC50 of less than 1 ng/ml. On the basis of time-of-addition experiments, JM3100 appeared to interact with a viral uncoating event, and this was further corroborated by an uncoating assay in which RNase sensitivity of [5-3H]uridine-labeled virions was monitored. In addition, but possibly mechanistically related, JM3100 blocks formation of infectious particles. JM3100 was also found to interfere directly with virus-induced syncytium formation, albeit at a higher concentration (1 to 2 microgram/ml) than that required for inhibition of viral replication. Following subcutaneous injection of 10 mg of JM3100 per kg of body weight to rabbits, anti-HIV activity was detected in serum corresponding to serum drug levels exceeding for at least 6 h by >100-fold the EC(50) required to inhibit HIV replication in vitro. When combined with either 3'-azido-2',3' -dideoxythymidine or 2',3' -dideoxyinosine, JM3100 achieved a additive inhibition of HIV replication, and when repeatedly subcultivated in the presence of JM3100, the virus remained sensitive to the compound for at least 30 passages (120 days) in cell culture.

CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers

“…AMD3100 possesses the highest anti-HIV activity among a series of bicyclams that were synthesized in the early 1990s. 64,84 AMD3100 is a specific antagonist of CXCL12 binding to CXCR4, inhibiting CXCL12-mediated calcium mobilization, chemotaxis and GTP binding, and does not cross-react with other chemokine receptors. 85 AMD3100 was initially considered to interfere with HIV-1 fusion or uncoating.…”

Inefficient fusion due to a lack of attachment receptor/co-receptor restricts productive human immunodeficiency virus type 1 infection in human hepatoma Huh7.5 cells

“…FITC-conjugated anti-CD4 mAb (clone RPA-T4) was purchased from eBioscience, PE-conjugated anti-CXCR4 mAb (clone 12G5) and PE-conjugated anti-CCR5 mAb (clone 5D7) from BD Biosciences, and the anti-GalCer mAb from Millipore. The following reagents were obtained through the AIDS Repository Reagent Program: EFV, a non-nucleoside reverse transcriptase inhibitor of HIV-1; 118-D-24, an integrase inhibitor (Svarovskaia et al, 2004); T-20, a fusion inhibitor; AMD-3100, an antagonist of CXCR4 (Bridger et al, 1995;De Clercq et al, 1994;Hendrix et al, 2000); and TAK-779, an antagonist of CCR5 (Baba et al, 1999).…”

Complex interplay of kinetic factors governs the synergistic properties of HIV-1 entry inhibitors

“…HongKui Deng and Dan Littman (63); Chessie 8 hybridoma from Dr. George Lewis (64); maraviroc (11580) (65,66); AMD-3100 (67,68); and TAK779 (69). HEK 293T cells were obtained from the ATCC.…”