ANTIVIRAL ACTIVITY OF THE BICYCLAM DERIVATIVE JM3100 AGAINST DRUG-RESISTANT STRAINS OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1

Bicyclams have recently been identified as potent and selective inhibi tors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication. The prototype of this series, JM3100 exhibits anti-HIV p otency at concentrations ranging from 0.001 to 0.01 mu g/ml. JM3100 pr oved to be active when tested against HIV strains resistant to the rev erse transcriptase (RT) inhibitors 3'-azido-3'-deoxythymidine (AZT), 2 ',3'-dideoxyinosine (DDI), 3TC, alpha APA and TIBO, at roughly the sam e concentrations as for the wild-type strain, The virus was passaged i n vitro in the presence of increasing concentrations of either TIBO or alpha APA alone or in combination with JM3100. The combination betwee n TIBO, or alpha APA, and JM3100 delayed the development of TIBO- and alpha APA-resistant strains, without emergence of resistance to JM3100 , In separate experiments, it took more than 60 passages (300 days) in MT-4 cells and 20 passages (140 days) in peripheral blood lymphocyte (PBL) cells For the virus to become resistant to JM3100, The JM3100-re sistant virus showed cross-resistance sulfated polysaccharides such as dextran sulfate (DS), pentosan sulfate (PS), heparin and cyclodextrin sulfate (CDS), suggesting that these compounds may share a common mec hanism of action. Furthermore, the inhibitory effect of JM3100 on viru s-induced syncytium formation was enhanced in the presence of heparin. The results presented here provide further support for the bicyclams as attractive candidate drugs for the chemotherapy of HIV infections.