ANTI-HIV TYPE-1 PROPERTIES OF CHEMICALLY-MODIFIED HEPARINS WITH DIMINISHED ANTICOAGULANT ACTIVITY

Several groups have reported that sulfated polysaccharides are potent and selective in vitro inhibitors of human immunodeficiency virus type 1 (HIV-1); however, their therapeutic application is limited by their anticoagulant activity. In view of possible improvements in therapeut ic potential, a number of heparin derivatives with reduced anticoagula nt activity were studied for their inhibitory activity of an HIV-depen dent syncytium formation assay, in comparison with standard anionic po lysaccharides, such as sodium heparin, dextran sulfate, and heparin su lfate. The chemical modifications introduced in the heparin molecule i ncluded succinylation of desulfated N groups (Suc-H), exhaustive perio date oxidation and reduction (RO-H), and controlled nitrous acid degra dation (LMW-H). The most pronounced anti-HIV activity was observed wit h RO-H, Suc30-H (standard heparin, 30% succinylated), and Suc100-LMW-H (low molecular weight heparin, 100% succinylated); the latter retaine d only 5% of the anticoagulant activity of standard heparin, whereas R O-H and Suc30-H retained approximately 35% of the anticoagulant activi ty of standard heparin. A safety ratio (arbitrary units of anti-HN act ivity per anticoagulant international unit) was calculated: by this pa rameter, RO-H, Suc30-H, and Suc100-LMW-H were, respectively, 48-, 3.6- , and 1644-fold more safe than standard heparin.