title: Chemically sulfated Escherichia coli K5 polysaccharide derivatives as extracellular HIV-1 Tat protein antagonists.
abstract: 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 alphav beta3 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.
authors.affiliation: Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Urbinati
authors.forename: Antonella
authors.initials: A
authors.lastname: Bugatti
authors.forename: Pasqua
authors.initials: P
authors.lastname: Oreste
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zoppetti
authors.forename: Johannes
authors.initials: J
authors.lastname: Waltenberger
authors.forename: Stefania
authors.initials: S
authors.lastname: Mitola
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Marco
authors.initials: M
authors.lastname: Presta
authors.forename: Marco
authors.initials: M
authors.lastname: Rusnati
mesh_terms: D000818:Animals; D016667:Bacterial Capsules; D002642:Chick Embryo; D004926:Escherichia coli / Q000737:chemistry*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000187:drug effects*; D011135:Polysaccharides, Bacterial / Q000737:chemistry / Q000494:pharmacology*; D013431:Sulfates / Q000737:chemistry; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D015696:Gene Products, tat; D011135:Polysaccharides, Bacterial; D013431:Sulfates; D054322:tat Gene Products, Human Immunodeficiency Virus; C050673:capsular polysaccharide K5