Chemically sulfated Escherichia coli K5 polysaccharide derivatives as extracellular HIV-1 Tat protein antagonists.
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.
Urbinati
Chiara
C
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
Bugatti
Antonella
A
Oreste
Pasqua
P
Zoppetti
Giorgio
G
Waltenberger
Johannes
J
Mitola
Stefania
S
Ribatti
Domenico
D
Presta
Marco
M
Rusnati
Marco
M
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
D015696:Gene Products, tat; D011135:Polysaccharides, Bacterial; D013431:Sulfates; D054322:tat Gene Products, Human Immunodeficiency Virus; C050673:capsular polysaccharide K5