Title: Potent in vitro anti-human immunodeficiency virus-1 activity of modified human serum albumins
Authors: Jansen, R W ×
Molema, G
Pauwels, R
Schols, Dominique
De Clercq, Erik
Meijer, D K #
Issue Date: Jun-1991
Series Title: Molecular Pharmacology vol:39 issue:6 pages:818-23
Abstract: A series of neoglycoproteins was synthesized by coupling of thiophosgene-activated p-aminophenyl derivatives [Biol. Cell. 47:95-110 (1983); J. Histochem. Cytochem. 32:1091-1094 (1984)] of various sugars to human serum albumin. The compounds were evaluated for their in vitro activity against human immunodeficiency virus (HIV). Neoglycoproteins with the highest sugar content were found to be the most potent inhibitors of HIV-1-induced cytopathogenicity. However, this was not due to the nature of the sugar used but, rather, was related to the extra negative charge of the neoglycoproteins. To investigate whether the antiviral activity of the neoglycoproteins exhibited sugar specificity, increased with increasing negative charge, or depended on both sugar specificity and negative charge, we synthesized albumins and neoglycoproteins with an enhanced negative charge, by treatment with formaldehyde or succinic anhydride. Succinylated human serum albumin had the most pronounced net negative charge and had an IC50 of about 1 microgram/ml. No cytotoxicity was observed at concentrations up to 1 mg/ml, implicating a selectivity index (CC50/IC50) of at least 10(3). To elucidate the mechanism of action of these anionic albumins, we investigated whether they interfered with HIV-1 adsorption to the cells, binding of anti-OKT4A monoclonal antibody (mAb) to the CD4 receptor, binding of anti-gp120 mAb to gp120, or inhibition of syncytium formation in co-cultures of HIV-1-infected HUT-78 cells with MOLT-4 cells. From these experiments, we conclude that albumins with an increased negative charge (a) are potent and nontoxic anti-HIV-1 agents, (b) cause a 50% reduction of syncytium formation in the same concentration range as their IC50 in the antiviral assay, and (c) do not bind to the OKT4A epitope of the CD4 receptor and only partly inhibit anti-gp120 mAb-gp120 interaction and virus-cell binding at concentrations that are 100 times higher than their IC50 in the antiviral assay. Therefore, we conclude that the modified albumins interfere with a post-binding event, of which one of the potential mechanisms is an interaction with the gp41 fusion protein, which is necessary for syncytium formation but is not involved in initial virus binding.
ISSN: 0026-895X
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

Files in This Item:

There are no files associated with this item.

Request a copy


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science