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 inhibitors of human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2) replication. The prototype of this series, JM3100 exhibits anti-HIV potency at concentrations ranging from 0.001 to 0.01 micrograms/ml. JM3100 proved to be active when tested against HIV strains resistant to the reverse transcriptase (RT) inhibitors 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), 3TC, alpha APA and TIBO, at roughly the same concentrations as for the wild-type strain. The virus was passaged in vitro in the presence of increasing concentrations of either TIBO or alpha APA alone or in combination with JM3100. The combination between 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-resistant virus showed cross-resistance to sulfated polysaccharides such as dextran sulfate (DS), pentosan sulfate (PS), heparin and cyclodextrin sulfate (CDS), suggesting that these compounds may share a common mechanism of action. Furthermore, the inhibitory effect of JM3100 on virus-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.
Esté
J A
JA
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Vreese
K
K
Witvrouw
M
M
Schmit
J C
JC
Vandamme
A M
AM
Anné
J
J
Desmyter
J
J
Henson
G W
GW
Bridger
G
G
De Clercq
E
E
D000998:Antiviral Agents / Q000494:pharmacology*; D001596:Benzylamines; D000080027:Cyclams; D004352:Drug Resistance, Microbial; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D000071228:Polyelectrolytes; D011108:Polymers / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D001596:Benzylamines; D000080027:Cyclams; D054303:HIV Reverse Transcriptase; D006571:Heterocyclic Compounds; D000071228:Polyelectrolytes; D011108:Polymers; D018894:Reverse Transcriptase Inhibitors; C088327:plerixafor