The Anti-HIV Pentameric Pseudopeptide HB-19 is Preferentially Taken up in vivo by Lymphoid Organs Where It Forms a Complex with Nucleolin

• Published in: Proceedings of the National Academy of Sciences - PNAS 2001-11, Vol.98 (24), p.14090-14095
• Main Authors: Krust, B., Vienet, R., Cardona, A., Rougeot, C., Jacotot, E., Callebaut, C., Guichard, G., Briand, J. P., Grognet, J. M., Hovanessian, A. G., Edelman, L.
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - isolation & purification; Anti-HIV Agents - metabolism; Anti-HIV Agents - pharmacokinetics; Anti-HIV Agents - pharmacology; Biological Sciences; Blood; Blood plasma; Bones; HB-19 protein; HeLa Cells; HIV; HIV-1; Human immunodeficiency virus; Humans; Kidneys; Liver; Lymphatic system; Lymphocytes; Lymphoid Tissue - metabolism; Male; Nuclear Proteins - metabolism; Nucleolin; Peptide Fragments - isolation & purification; Peptide Fragments - metabolism; Peptide Fragments - pharmacokinetics; Peptide Fragments - pharmacology; Peptides; Pharmacology; Phosphoproteins - metabolism; Proteins - isolation & purification; Proteins - metabolism; Proteins - pharmacokinetics; Proteins - pharmacology; Radioactive decay; Rats; Rats, Wistar; RNA-Binding Proteins - metabolism; Spleen; Tissue Distribution; Urine
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.221467298

The HB-19 pseudopeptide 5[Kψ(CH2N)PR]-TASP, ψ(CH2N) for reduced peptide bond, is a specific inhibitor of HIV infection in different CD4+cell lines and in primary T-lymphocytes and macrophages. It blocks virus-particle attachment to permissive cells by binding and forming a stable complex with nucleolin expressed on the cell surface. Here, we have investigated the tissue distribution of the tritiated HB-19 by using β-radio imager whole-body mapping in rats. A rapid, selective, and stable distribution and accumulation of the systematically administered HB-19 was demonstrated within the spleen, liver, bone, and kidney as soon as 5 min following its administration. No apparent uptake of HB-19 occurred in the brain and the muscle tissue. Interestingly and despite its rapid clearance from the blood, at 24 h postexposure a significant proportion of HB-19 was still recovered from target organs, of which 16-37% could be acounted for intact pseudopeptide. The elimination of HB-19 mainly occurred by renal glomerular filtration and most of the excreted radioactivity appeared to be HB-19 metabolites. Finally, injection of the biotin-labeled HB-19 pseudopeptide but not its control counterpart allowed the recovery of the HB-19-nucleolin complex from the liver, spleen, thymus, and bone marrow, thus indicating that the in vivo molecular target of HB-19 is surface nucleolin. Our results demonstrate the preferential uptake and stability of HB-19 in lymphoid organs that are the site of HIV propagation.