RT Journal Article
SR Electronic
T1 Polyanionic (i.e., Polysulfonate) Dendrimers Can Inhibit the Replication of Human Immunodeficiency Virus by Interfering with Both Virus Adsorption and Later Steps (Reverse Transcriptase/Integrase) in the Virus Replicative Cycle
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1100
OP 1108
DO 10.1124/mol.58.5.1100
VO 58
IS 5
A1 Myriam Witvrouw
A1 Valery Fikkert
A1 Wim Pluymers
A1 Barry Matthews
A1 Karen Mardel
A1 Dominique Schols
A1 John Raff
A1 Zeger Debyser
A1 Erik De Clercq
A1 George Holan
A1 Christophe Pannecouque
YR 2000
UL http://molpharm.aspetjournals.org/content/58/5/1100.abstract
AB Polyanionic dendrimers were synthesized and evaluated for their antiviral effects. Phenyldicarboxylic acid (BRI6195) and naphthyldisulfonic acid (BRI2923) dendrimers were found to inhibit the replication of human immunodeficiency virus type 1 (HIV-1; strain IIIB) in MT-4 cells at a EC50 of 0.1 and 0.3 μg/ml, respectively. The dendrimers were not toxic to MT-4 cells up to the highest concentrations tested (250 μg/ml). These compounds were also effective against various other HIV-1 strains, including clinical isolates, HIV-2 strains, simian immunodeficiency virus (SIV, strain MAC251), and HIV-1 strains that were resistant to reverse transcriptase inhibitors. HIV strains containing mutations in the envelope glycoprotein gp120 (engendering resistance to known adsorption inhibitors) displayed reduced sensitivity to the dendrimers. The compounds inhibited the binding of wild-type virus and recombinant virus (containing wild-type gp120) to MT-4 cells at concentrations comparable to those that inhibited the replication of HIV-1(IIIB) in these cells. Cellular uptake studies indicated that BRI2923, but not BRI6195, permeates into MT-4 and CEM cells. Accordingly, the naphtyldisulfonic acid dendrimer (BRI2923) proved able to inhibit later steps of the replication cycle of HIV, i.e., reverse transcriptase and integrase. NL4.3 strains resistant to BRI2923 were selected after passage of the virus in the presence of increasing concentrations of BRI2923. The virus mutants showed 15-fold reduced sensitivity to BRI2923 and cross-resistance to known adsorption inhibitors. However, these virus mutants were not cross-resistant to reverse transcriptase inhibitors or protease inhibitors. We identified several mutations in the envelope glycoprotein gp120 gene (i.e., V2, V3, and C3, V4, and C4 regions) of the BRI2923-resistant NL4.3 strains that were not present in the wild-type NL4.3 strain, whereas no mutations were found in the reverse transcriptase or integrase genes.