Novel Polysulfated Galactose-Derivatized Dendrimers as Binding Antagonists of Human Immunodeficiency Virus Type 1 Infection

Abstract

Evidence indicates that galactosyl ceramide (GalCer) and its 3-sulfated derivative, sulfatide (SGalCer), may act as alternate coreceptors for human immunodeficiency virus type 1 (HIV-1) in CD4 ؊ cells. Glycosphingolipids (GSLs) may also be necessary for fusion of HIV-1 and host cell membranes. Using an enzyme-linked immunosorbent assay to determine which GSL was the best ligand for both recombinant and virus-associated gp120, we found that SGalCer was the best ligand for each rgp120 and HIV-1 isolate tested. Therefore, novel multivalent glycodendrimers, which mimic the carbohydrate clustering reportedly found in lipid rafts, were synthesized based on the carbohydrate moiety of SGalCer. Here we describe the synthesis of a polysulfated galactose functionalized, fifth generation DAB dendrimer (PS Gal 64mer), containing on average two sulfate groups per galactose residue. Its ability to inhibit HIV-1 infection of cultured indicator cells was compared to that of dextran sulfate (DxS), a known, potent, binding inhibitor of HIV-1. The results indicate that the PS Gal 64mer inhibited infection by the HIV-1 isolates tested as well as DxS.

Dendrimers in Anti-HIV Therapy

“…The first attempt to use this concept was in 2000, when multivalent polysulfated PPI glycodendrimers were tested as binding antagonists of the virus. Results indicated similar inhibitory and cytotoxicity properties as dextran sulfate [Kensinger et al, 2004]. More recent in vitro studies have demonstrated that HIV-1 inhibitory properties of compounds, based on phosphonic acid terminated dendrimers and N-hexadecylamino lactitol moieties, make them promising anti-HIV drug candidates.…”

Polymeric Anti‐HIV Therapeutics

“…[84] Third, fourth and fifth generation glycodendrimers that display 16, 32 and 64 randomly sulfated galactose moieties (21) respectively, are very effective inhibitors of R5 and X4 tropic HIV-1. [85,86] Kensinger et al determined that the size and degree of sulfation of the glycodendrimer directly correlates with its efficacy against HIV-1 BaL (R5-tropic virus). Interestingly, despite the nanomolar affinities of the non-sulfated glycodendrimers for recombinant gp120 obtained via surface plasmon resonance (SPR), poor inhibition of HIV-1 infectivity was observed.…”

“…Taken together with low overall cytotoxicity and the possibility to functionalize the dendrimers with more than one moiety suggested that these compounds are ideal carriers of potential inhibitors. [86] Second generation PAMAM dendrimers functionalized with sulfated sialic acid (22) were also shown to possess efficacy against four different HIV-1 variants. However, only low micromolar efficacies were obtained, compared to low nanomolar efficacies obtained with 500 kDa dextran sulfate.…”

Role of sulfatide in virus infection and replication

“…The inability of gp120 to penetrate into a mixed monolayer of GalCer and sulfatide indicates that sulfatide competes with GalCer for gp120 binding. The binding of recombinant gp120 to sulfatide exhibits the strongest activity of all tested glycolipids, including GalCer (19). The attachment of HIV-1 to sulfatide ＋ /GalCer ＋ cells may proceed through predominant binding to sulfatide.…”