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Abstract
Multivalent compounds functionalized with the carbohydrate headgroups of immune cell-surface GSLs as inhibitors of HIV-1 infection.
Rosa Borges A.1, Puri A.2, Krebs F.C.3, Wigdahl B.3, Blumenthal R.2, Rawat S.S.2, Johnson B.T.2, Schengrund C.-L.1
1Penn State University, College of Medicine, Hershey, Pennsylvania, United States of America, 2Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America, 3Drexel University, College of Medicine, Philadelphia, Pennsylvania, United States of America
Introduction: In addition to CD4 and the chemokine coreceptors CCR5 and CXCR4, glycosphingolipids (GSLs) are needed for productive infection of cells by HIV-1. Since GSLs are often found localized in lipid rafts on the cell surface, their carbohydrate head groups are clustered together and may provide a platform for virus-cell surface interactions. Because protein-carbohydrate interactions often require multiple ligands, we hypothesized that multivalent carbohydrate molecules would inhibit viral infection of cells.
Methods: Globotriose and 3´-sialyllactose were linked to dendrimer scaffolds. After linking each carbohydrate to different generations of dendrimers, MALDI-TOF MS was used to determine the average mass of each derivative. The mass was then used to calculate the average number of sugar units on each dendrimer. Using a live virus in vitro infection assay, the ability of each glycodendrimer to inhibit viral infection was compared to that of dextran sulfate. Cell viability studies were done to determine glycodendrimer toxicity
Results: R5, X4, and X4R5 isolates showed varying levels of inhibition dependent on use of either globotriose- or 3´-sialyllactose-derivatized dendrimers. EC50s of effective glycodendrimers ranged from sub-µM to sub-nM, values equivalent to, and sometimes better than, values obtained for dextran sulfate, a known inhibitor of viral infection. Cell viability studies indicated that none of the compounds were cytotoxic at concentrations less than 1 mg/ml.
Conclusions: The results show that multivalent carbohydrates carrying globotriose or 3´-sialyllactose moieties were effective inhibitors of HIV-1 infection of cells in vitro. More interestingly, inhibition of viral infection by our glycodendrimers suggests there may be a viral tropism dependence for cell-surface carbohydrates. These observations provide a novel approach for the design of new carbohydrate-based antiviral drugs. Based on their water-solubility, low cytotoxicity, and potent inhibition of cellular infection, these glycodendrimers merit consideration as prototypes for use in microbicide development, and possibly novel HIV-1 drug therapy.
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