title: Protein binding of human immunodeficiency virus protease inhibitor KNI-272 and alteration of its in vitro antiretroviral activity in the presence of high concentrations of proteins.
abstract: KNI-272 represents a peptide-based protease inhibitor having potent antiretroviral activity against human immunodeficiency virus (HIV) in vitro. The structure contains allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] with a hydroxymethylcarbonyl isostere. We asked whether this experimental anti-HIV agent could exert its activity in vitro in the presence of relatively high concentrations of fetal calf serum (FCS) and assessed its protein-binding properties by using fresh human plasma preparations. The 50 and 75% inhibitory concentrations of KNI-272 against HIV type 1 replication in vitro were 3- to 5-fold and 5-fold higher in the presence of 50% FCS and 15- to 25-fold and 25- to 100-fold higher in the presence of 80% ECS, respectively, than those with 15% FCS, whereas the antiviral activity of 2',3'-dideoxyinosine was not significantly affected by FCS concentrations in the culture. Detailed studies of the protein binding of KNI-272 suggest that in human plasma binding occurs predominantly to alpha 1-acid glycoprotein and that KNI-272 is probably extensively (approximately 98 to 99%) protein bound at concentrations likely to be achieved in the circulation. Thus, higher levels of KNI-272 in plasma may be required when this compound undergoes clinical trials relative to those inferred from in vitro data involving the use of 10 to 15% FCS-containing culture media. The current data may have a relevance to other antiretroviral drugs that are under development and that have a high protein-binding capacity.
authors.affiliation: Experimental Retrovirology, Section, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: S
authors.initials: S
authors.lastname: Kageyama
authors.forename: B D
authors.initials: BD
authors.lastname: Anderson
authors.forename: B L
authors.initials: BL
authors.lastname: Hoesterey
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
authors.forename: K P
authors.initials: KP
authors.lastname: Flora
authors.forename: H
authors.initials: H
authors.lastname: Mitsuya
mesh_terms: D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D002417:Cattle; D002478:Cells, Cultured; D017320:HIV Protease Inhibitors / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D007202:Indicators and Reagents; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D009961:Orosomucoid / Q000378:metabolism; D011485:Protein Binding; D011506:Proteins / Q000494:pharmacology*; D012190:Retroviridae / Q000187:drug effects*
chemical_list: D001798:Blood Proteins; D017320:HIV Protease Inhibitors; D007202:Indicators and Reagents; D009842:Oligopeptides; D009961:Orosomucoid; D011506:Proteins; C077822:kynostatin 272