Anti-HIV Type 1 Properties of Chemically Modified Heparins with Diminished Anticoagulant Activity

Abstract

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 therapeutic potential, a number of heparin derivatives with reduced anticoagulant activity were studied for their inhibitory activity of an HIV-dependent syncytium formation assay, in comparison with standard anionic polysaccharides, such as sodium heparin, dextran sulfate, and heparin sulfate. The chemical modifications introduced in the heparin molecule included succinylation of desulfated N groups (Suc-H), exhaustive periodate oxidation and reduction (RO-H), and controlled nitrous acid degradation (LMW-H). The most pronounced anti-HIV activity was observed with RO-H, Suc30-H (standard heparin, 30% succinylated), and Suc100-LMW-H (low molecular weight heparin, 100% succinylated); the latter retained only 5% of the anticoagulant activity of standard heparin, whereas RO-H and Suc30-H retained approximately 35% of the anticoagulant activity of standard heparin. A safety ratio (arbitrary units of anti-HIV activity per anticoagulant international unit) was calculated: by this parameter, RO-H, Suc30-H, and Suc100-LMW-H were, respectively, 48-, 3.6-, and 1644-fold more safe than standard heparin.

Interaction of HIV-1 Tat Protein with Heparin

“…To this respect, it is interesting to note that sulfated polysaccharides, including heparin and dextran sulfate, have been reported to be effective in vitro inhibitors of HIV infection (76,77). Sulfated polysaccharides may act at the level of viral binding and penetration into the host cell (78) and prevent gp120-CD4 interaction (79). Our data rise the possibility that sulfated polysaccharides may inhibit HIV replication also by inhibiting Tat activity.…”

The Basic Domain in HIV-1 Tat Protein as a Target for Polysulfonated Heparin-mimicking Extracellular Tat Antagonists

“…ϩ -sensitive cells (88) as a consequence of their capacity to disrupt gp120 interaction with CD4 (89,90) and/or with cell-associated HS (91,92). Also, polysulfated polysaccharides prevent syncytium formation between HIV-infected and uninfected cells (89,90).…”

“…Also, polysulfated polysaccharides prevent syncytium formation between HIV-infected and uninfected cells (89,90). This may explain the capacity of polysulfated polysaccharides to inhibit HIV-1 replication and cytopathogenicity in different experimental models (reviewed in Ref.…”

Heparin-Mimicking Sulfonic Acid Polymers as Multitarget Inhibitors of Human Immunodeficiency Virus Type 1 Tat and gp120 Proteins

“…In effect, unmodified, chemically modified, and biotechnological heparins (41,59), suramin and distamycine derivatives (47), pentosan polysulfate (48), and dextrin-2-sulfate (62) have been demonstrated to bind Tat and to inhibit some of its biological activities. Similarly, unmodified, chemically modified, and biotechnological heparins (28,33,60), dextran sulfate (52), suramin (50), distamycine derivatives (10), and pentosan polysulfate (30) have been demonstrated to bind gp120, inhibiting HIV infection. No attempt has yet been made to evaluate polyanions as antagonists of the extracellular free form of gp120.…”