Sulfated Alkyl Oligosaccharides Inhibit Human Immunodeficiency virus in vitro and Provide Sustained Drug Levels in Mammals

Abstract

This study provides an estimate of the relative anti-human immunodeficiency virus (HIV) activities of synthetic sulfated alkyl oligosaccharides in vitro and of their mechanism of action, and an assessment of the levels of alkyl oligosaccharides in small mammals. The antiviral activities of the compounds against several human immunodeficiency virus type-1 and type-2 strains were determined in human CD4⁺ cells, including primary lymphocytes and macrophages. Laser flow cytometry and a cell-based syncytium assay were used to elucidate the anti-binding/fusion properties of the oligosaccharides. The sulfated alkyl laminarioligosaccharide DL-110 was shown to be the most potent and selective anti-HIV agent in culture with a median inhibitory concentration of 0.2 μM in primary human lymphocytes. This compound did not markedly interact with the CD4⁺ receptor on lymphocytes at 50 μM, but demonstrated potent anti-syncytium properties in vitro at submicromolar concentrations. DL-110 had no anti-coagulation activity at 38 μM. Mice, rabbits and beagle dogs were given an intravenous injection of test compounds and the drug levels in serum were quantified. When 32 mg kg⁻¹ of DL-110 was administered to mice, significant antiviral concentrations in serum were achieved even 12 h after treatment. Similarly, prolonged antiviral effects were noted in rabbits and dogs 24 h after injection of DL-110. The half-life of DL-110 in mice, rabbits and dogs was estimated to be 5 h. DL-110 and some of its derivatives are promising candidates for further evaluation of the prophylaxis and therapy of HIV infections.