Chemically sulfated Escherichia coli K5 polysaccharide derivatives as extracellular HIV-1 Tat protein antagonists

• Published in: FEBS letters 2004-06, Vol.568 (1), p.171-177
• Main Authors: Urbinati, Chiara, Bugatti, Antonella, Oreste, Pasqua, Zoppetti, Giorgio, Waltenberger, Johannes, Mitola, Stefania, Ribatti, Domenico, Presta, Marco, Rusnati, Marco
• Format: Article
• Language: English
• Subjects: Animals; Antagonist; Bacterial Capsules; bTat, biotinilated Tat; CAM, chick embryo chorioallantoic membrane; CAT, chloramphenicol acetyltransferase; Chick Embryo; CHO cells, Chinese hamster ovary cells; ECs, endothelial cells; Escherichia coli; Escherichia coli - chemistry; FGF, fibroblast growth factor; GAG, glycosaminoglycan; Gene Products, tat - antagonists & inhibitors; GFP, green fluorescent protein; GlcA, glucuronic acid; GlcN, glucosamine; GlcNAc, N-acetyl-glucosamine; GST, glutathione S-transferase; HIV; HIV Long Terminal Repeat; HIV-1 - drug effects; HSPGs, heparan sulfate proteoglycans; Human immunodeficiency virus 1; K5 polysaccharide; K5-N,OS(H), N,O-sulfated K5 with high degree of sulfation; K5-N,OS(L), N,O-sulfated K5 with low degree of sulfation; K5-NS, N-sulfated K5; K5-OS(H), O-sulfated K5 with high degree of sulfation; K5-OS(L), O-sulfated K5 with low degree of sulfation; KDR, vascular endothelial growth factor receptor 2; LTR, long terminal repeats; Polyanion; Polysaccharides, Bacterial - chemistry; Polysaccharides, Bacterial - pharmacology; Sulfates - chemistry; Tat; tat Gene Products, Human Immunodeficiency Virus; VEGF, vascular endothelial growth factor; VN, vitronectin; xcTat, extracellular Tat
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2004.05.033

The HIV-1 transactivating factor (Tat) acts as an extracellular cytokine on target cells, including endothelium. Here, we report about the Tat-antagonist capacity of chemically sulfated derivatives of the Escherichia coli K5 polysaccharide. O-sulfated K5 with high sulfation degree (K5-OS(H)) and N, O-sulfated K5 with high (K5-N,OS(H)) or low (K5-N,OS(L)) sulfation degree, but not unmodified K5, N-sulfated K5, and O-sulfated K5 with low sulfation degree, bind to Tat preventing its interaction with cell surface heparan sulfate proteoglycans, cell internalization, and consequent HIV-LTR-transactivation. Also, K5-OS(H) and K5-N,OS(H) prevent the interaction of Tat to the vascular endothelial growth factor receptor-2 on endothelial cell (EC) surface. Finally, K5-OS(H) inhibits α vβ 3 integrin/Tat interaction and EC adhesion to immobilized Tat. Consequently, K5-OS(H) and K5-N,OS(H) inhibit the angiogenic activity of Tat in vivo. In conclusion, K5 derivatives with distinct sulfation patterns bind extracellular Tat and modulate its interaction with cell surface receptors and affect its biological activities. These findings provide the basis for the design of novel extracellular Tat antagonists with possible implications in anti-AIDS therapies.