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

Abstract

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.

Polymeric Anti‐HIV Therapeutics

“…The resulting amines were modified with sodium 3,6-disulfonaphthyl isothiocyanate or 3,5-dicarboxyphenyl isothiocyanate to form polysulfate or polycarboxylate functionalized dendrimers (18,19), respectively. [83] The polysulfate functionalized PAMAM dendrimers (19) showed to be effective against HIV-1 and HIV-2 with efficacies similar to those observed with dextran sulfate (1). Additionally, the polysulfate dendrimers were also effective against HIV strains that were resistant to 1 and AMD-3100 (bicyclam derivative that is a candidate CXCR4 antagonist).…”

“…Additionally, the polysulfate dendrimers were also effective against HIV strains that were resistant to 1 and AMD-3100 (bicyclam derivative that is a candidate CXCR4 antagonist). [83] Compared to the polysulfate functionalized PAMAM dendrimers, the polycarboxylate functionalized PAMAM dendrimers (19) were equally effective for HIV-1 but significantly less effective against strains of HIV-2. Analogous to dendrimers based on PAMAM, a 4 th generation poly(L-lysine) dendrimer modified with 32 3,6-disulfonaphthyl groups (20) has shown to be an effective inhibitor against infection of various clades of HIV-1.…”

Dendrimers in Anti-HIV Therapy

“…Owing to the different cell penetration rates of BRI6195 and BRI2923 compounds, the latter was demonstrated to exhibit another antiviral activity during reverse transcription and integration steps. Unfortunately, it has been found that some gp120 mutations display inconsistency, preventing the described PAMAM dendrimers from completely and successfully curing patients after treating cells [Witvrouw, 2000].…”

Hyperbranched Molecular Structures with Potential Antiviral Activity: Derivatives of 5,6-Dihydroxyindole-2-Carboxylic Acid

“…As far as dendrimers are concerned, their applications in treatment of several human diseases are under critical investigation and looks very promising; these macromolecules serve as targeted drug, carriers and delivery agents as well as imaging agents in human systems [4][5][6]. In particular, polymers having a dendrimer-based structure have emerged from several research programs focused on the development of inhibitors of HIV and other enveloped viruses [7][8][9][10][11][12][13][14][15][16][17][18][19].…”