title: 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.
authors.affiliation: Centro San Luigi, Istituto Scientifico H San Raffaele, Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Lopalco
authors.forename: F
authors.initials: F
authors.lastname: Ciccomascolo
authors.forename: P
authors.initials: P
authors.lastname: Lanza
authors.forename: G
authors.initials: G
authors.lastname: Zoppetti
authors.forename: I
authors.initials: I
authors.lastname: Caramazza
authors.forename: F
authors.initials: F
authors.lastname: Leoni
authors.forename: A
authors.initials: A
authors.lastname: Beretta
authors.forename: A G
authors.initials: AG
authors.lastname: Siccardi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects*; D002240:Carbohydrate Sequence; D002478:Cells, Cultured; D016264:Dextran Sulfate / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000276:immunology; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000737:chemistry / Q000494:pharmacology*; D006497:Heparan Sulfate / Q000737:chemistry / Q000494:pharmacology*; D008969:Molecular Sequence Data; D008970:Molecular Weight
chemical_list: D000911:Antibodies, Monoclonal; D016264:Dextran Sulfate; D015699:HIV Envelope Protein gp120; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight; D006497:Heparan Sulfate