BSA conjugates bearing multiple copies of the basic domain of HIV-1 Tat: Prototype for the development of multitarget inhibitors of extracellular Tat

Antiviral Res. 2010 Jul;87(1):30-9. doi: 10.1016/j.antiviral.2010.04.004. Epub 2010 Apr 14.


The transactivating factor (Tat) of HIV-1 is involved in AIDS progression and associated pathologies. Tat possesses a basic amino acid sequence implicated in heparan sulfate proteoglycan (HSPG)-mediated internalization, nuclear localization and transactivation by Tat and in the interaction of Tat with integrins and with the vascular endothelial growth factor receptor 2 (KDR) (kinase insert domain receptor). A BSA conjugate bearing an average of four copies of a peptide representing the basic domain/nuclear localization signal of Tat (BSA-Tat-NLS) inhibits transactivation by Tat exogenously added to cells but not by Tat endogenously produced after cell transfection with a tat cDNA, indicating that BSA-Tat-NLS does not interfere with Tat at an intracellular level. Surface plasmon resonance (SPR) experiments revealed that BSA-Tat-NLS binds to the HSPG analogue heparin. Accordingly, BSA-Tat-NLS binds to HSPGs of HL3T1 cell surface and inhibits HSPG-dependent Tat internalization. BSA-Tat-NLS retains its inhibitory potential when pre-incubated with HL3T1 cells before Tat administration, possibly by masking cell-surface HSPGs thus preventing Tat binding and internalization. SPR experiments revealed that BSA-Tat-NLS binds also to integrin alpha(v)beta(3) and KDR. Accordingly, it inhibits pro-angiogenic endothelial cell adhesion to Tat and motogenesis. In conclusion, BSA-Tat-NLS binds/masks three different cell-surface receptors of Tat inhibiting different biological activities. These data point to BSA-Tat-NLS as a prototype for the development of Tat-antagonists endowed with a multitargeted mechanism of action.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • HIV Fusion Inhibitors / chemistry
  • HIV Fusion Inhibitors / pharmacology*
  • HIV-1 / drug effects*
  • HIV-1 / physiology
  • HeLa Cells
  • Heparin / metabolism
  • Humans
  • Protein Binding
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / pharmacology*
  • Surface Plasmon Resonance
  • Virus Internalization / drug effects*
  • tat Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
  • tat Gene Products, Human Immunodeficiency Virus / chemistry
  • tat Gene Products, Human Immunodeficiency Virus / pharmacology*


  • HIV Fusion Inhibitors
  • tat Gene Products, Human Immunodeficiency Virus
  • Serum Albumin, Bovine
  • Heparin