HIGHLY POTENT AND SELECTIVE-INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS BY THE BICYCLAM DERIVATIVE JM3100

Bicyclams, in which the cyclam (1,4,8,11-tetraazacyclotetradecane) moi eties are tethered via an aliphatic bridge (i.e., propylene, as in JM2 763) are potent and selective inhibitors of human immunodeficiency vir us type 1 (HIV-1) and type 2 (HIV-2) (E. De Clercq, N. Yamamoto, R. Pa uwels, 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 89:5286-5290,19 92). We have now found that the bicyclam JM3100, in which the cyclam m oieties are tethered by an aromatic bridge [i.e., phenylenebis(methyle ne)], inhibits the replication of various HIV-1 and HIV-2 strains in v arious cell lines at a 50% effective concentration (EC50) of 1 to 10 n g/ml, which is about 100-fold lower than the concentration required fo r JM2763 to inhibit HIV replication and at least 100,000-fold lower th an the cytotoxic concentration (>500 mug/ml). In primary T4 lymphocyte s or primary monocytes, JM3100 proved inhibitory to HIV-1(III(B)) and several clinical HIV-1 isolates at an EC50 of less than 1 ng/ml. On th e basis of time-of-addition experiments, JM3100 appeared to interact w ith a viral uncoating event, and this was further corroborated by an u ncoating assay in which RNase sensitivity of [5-H-3]uridine-labeled vi rions was monitored. In addition, but possibly mechanistically related , JM3100 blocks formation of infectious particles. JM3100 was also fou nd to interfere directly with virus-induced syncytium formation, albei t at a higher concentration (1 to 2 mug/ml) than that required for inh ibition of viral replication. Following subcutaneous injection of 10 m g of JM3100 per kg of body weight to rabbits, anti-HIV activity was de tected in serum corresponding to serum drug levels exceeding for at le ast 6 h by > 100-fold the EC50 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 repli cation, and when repeatedly subcultivated in the presence of JM3100, t he virus remained sensitive to the compound for at least 30 passages ( 120 days) in cell culture.