The anti-HIV pentameric pseudopeptide HB-19 is preferentially taken up in vivo by lymphoid organs where it forms a complex with nucleolin.
The HB-19 pseudopeptide 5[Kpsi(CH(2)N)PR]-TASP, psi(CH(2)N) 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 beta-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 accounted 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.
Krust
B
B
Unité de Virologie et Immunologie Cellulaire, Unité de Recherche Associée 1930 Centre National de Recherche Scientifique (CNRS), 28 Rue du Dr Roux, 75714 Paris Cedex 15, France.
Vienet
R
R
Cardona
A
A
Rougeot
C
C
Jacotot
E
E
Callebaut
C
C
Guichard
G
G
Briand
J P
JP
Grognet
J M
JM
Hovanessian
A G
AG
Edelman
L
L
D000818:Animals; D019380:Anti-HIV Agents / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1; D006367:HeLa Cells; D006801:Humans; D008221:Lymphoid Tissue / Q000378:metabolism; D008297:Male; D009687:Nuclear Proteins / Q000378:metabolism*; D010446:Peptide Fragments / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D010455:Peptides; D010750:Phosphoproteins / Q000378:metabolism*; D011506:Proteins / Q000302:isolation & purification / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D000097796:Nucleolin
D019380:Anti-HIV Agents; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D010750:Phosphoproteins; D011506:Proteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C121944:HB-19 peptide