Pentosan Polysulfate as an Inhibitor of Extracellular HIV-1 Tat

Marco Rusnati, Chiara Urbinati, Antonella Caputo, Laura Possati, Hugues Lortat-Jacob, Mauro Giacca, Domenico Ribatti, Marco Presta

Research output: Contribution to journalArticlepeer-review


HIV-1 Tat protein, released from HIV-infected cells, may act as a pleiotropic heparin-binding growth factor. From this observation, extracellular Tat has been implicated in the pathogenesis of AIDS and of AIDS-associated pathologies. Here we demonstrate that the heparin analog pentosan polysulfate (PPS) inhibits the interaction of glutathione S-transferase (GST)-Tat protein with heparin immobilized to a BIAcore sensor chip. Competition experiments showed that Tat-PPS interaction occurs with high affinity (Kd = 9.0 nM). Also, GST·Tat prevents the binding of [3H]heparin to GST·Tat immobilized to glutathione-agarose beads. In vitro, PPS inhibits GST·Tat internalization and, consequently, HIV-1 long terminal repeat transactivation in HL3T1 cells. Also, PPS inhibits cell surface interaction and mitogenic activity of GST·Tat in murine adenocarcinoma T53 Tat-less cells. In all assays, PPS exerts its Tat antagonist activity with an ID 50 equal to ∼1.0 nM. In vivo, PPS inhibits the neovascularization induced by GST-Tat or by Tat-overexpressing T53 cells in the chick embryo chorioallantoic membrane. In conclusion, PPS binds Tat protein and inhibits its cell surface interaction, internalization, and biological activity in vitro and in vivo. PPS may represent a prototypic molecule for the development of novel Tat antagonists with therapeutic implications in AIDS and AIDS-associated pathologies, including Kaposi's sarcoma.

Original languageEnglish
Pages (from-to)22420-22425
Number of pages6
JournalJournal of Biological Chemistry
Issue number25
Publication statusPublished - Jun 22 2001

ASJC Scopus subject areas

  • Biochemistry


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