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

Mol Pharmacol. 2000 Nov;58(5):1100-8.


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 III(B)) in MT-4 cells at a EC(50) of 0.1 and 0.3 microg/ml, respectively. The dendrimers were not toxic to MT-4 cells up to the highest concentrations tested (250 microg/ml). These compounds were also effective against various other HIV-1 strains, including clinical isolates, HIV-2 strains, simian immunodeficiency virus (SIV, strain MAC(251)), 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(III(B)) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-HIV Agents / pharmacokinetics
  • Anti-HIV Agents / pharmacology*
  • Carboxylic Acids / pharmacokinetics
  • Carboxylic Acids / pharmacology
  • Cells, Cultured
  • Dendrimers
  • HIV Envelope Protein gp120 / metabolism
  • HIV Integrase / drug effects
  • HIV Integrase / metabolism
  • HIV Reverse Transcriptase / drug effects
  • HIV Reverse Transcriptase / metabolism
  • HIV-1 / classification
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • HIV-2 / drug effects
  • HIV-2 / physiology
  • Microscopy, Confocal
  • Mutation
  • Naphthalenes / pharmacokinetics
  • Naphthalenes / pharmacology
  • Polymers / pharmacokinetics
  • Polymers / pharmacology*
  • Rabbits
  • Sulfones / pharmacokinetics
  • Sulfones / pharmacology*
  • Sulfonic Acids
  • Thiourea / analogs & derivatives
  • Thiourea / pharmacokinetics
  • Thiourea / pharmacology
  • Time Factors
  • Virus Replication / drug effects*


  • Anti-HIV Agents
  • BRI 2923
  • BRI 6195
  • Carboxylic Acids
  • Dendrimers
  • HIV Envelope Protein gp120
  • Naphthalenes
  • Polymers
  • Sulfones
  • Sulfonic Acids
  • polysulfone P 1700
  • HIV Integrase
  • HIV Reverse Transcriptase
  • Thiourea