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

Chiara Urbinati, Antonella Bugatti, Pasqua Oreste, Giorgio Zoppetti, Johannes Waltenberger, Stefania Mitola, Domenico Ribatti, Marco Presta, Marco Rusnati

Research output: Contribution to journalArticle

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 αvβ3 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.

Original languageEnglish
Pages (from-to)171-177
Number of pages7
JournalFEBS Letters
Volume568
Issue number1-3
DOIs
Publication statusPublished - Jun 18 2004

Keywords

  • bTat, biotinilated Tat
  • CAM, chick embryo chorioallantoic membrane
  • CAT, chloramphenicol acetyltransferase
  • CHO cells, Chinese hamster ovary cells
  • ECs, endothelial cells
  • FGF, fibroblast growth factor
  • GAG, glycosaminoglycan
  • GFP, green fluorescent protein

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

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  • Cite this

    Urbinati, C., Bugatti, A., Oreste, P., Zoppetti, G., Waltenberger, J., Mitola, S., Ribatti, D., Presta, M., & Rusnati, M. (2004). Chemically sulfated Escherichia coli K5 polysaccharide derivatives as extracellular HIV-1 Tat protein antagonists. FEBS Letters, 568(1-3), 171-177. https://doi.org/10.1016/j.febslet.2004.05.033