Pentosan polysulfate as an inhibitor of extracellular HIV-1 Tat

Citation
M. Rusnati et al., Pentosan polysulfate as an inhibitor of extracellular HIV-1 Tat, J BIOL CHEM, 276(25), 2001, pp. 22420-22425
Citations number
42
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
276
Issue
25
Year of publication
2001
Pages
22420 - 22425
Database
ISI
SICI code
0021-9258(20010622)276:25<22420:PPAAIO>2.0.ZU;2-I
Abstract
HIV-1 Tat protein, released from HIV-infected cells, may act as a pleiotrop ic heparin-binding growth factor. From this observation, extracellular Tat has been implicated in the pathogenesis of AIDS and of AIDS-associated path ologies. Here we demonstrate that the heparin analog pentosan polysulfate ( PPS) inhibits the interaction of glutathione S-transferase (GST)-Tat protei n with heparin immobilized to a BIAcore sensor chip. Competition experiment s showed that Tat-PPS interaction occurs with high affinity (K-d = 9.0 nM). Also, GST.Tat prevents the binding of [H-3]heparin to GST Tat immobilized to glutathione-agarose beads. In vitro, PPS inhibits GST Tat internalizatio n and, consequently, HIV-1 long terminal repeat transactivation in HL3T1 ce lls. Also, PPS inhibits cell surface interaction and mitogenic activity of GST Tat in murine adenocarcinoma T53 Tat-less cells. In all assays, PPS exe rts its Tat antagonist activity with an ID50 equal to similar to1.0 nM. In vivo, PPS inhibits the neovascularization induced by GST Tat or by Tat over expressing T53 cells in the chick embryo chorioallantoic membrane. In concl usion, PPS binds Tat protein and inhibits its cell surface interaction, int ernalization, and biological activity in vitro and in vivo. PPS may represe nt a prototypic molecule for the development of novel Tat antagonists with therapeutic implications in AIDS and AIDS-associated pathologies, including Kaposi's sarcoma.