Document 0503
 DOCN  M9490503
 TI    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.
 DT    9411
 AU    Kageyama S; Anderson BD; Hoesterey BL; Hayashi H; Kiso Y; Flora KP;
       Mitsuya H; Experimental Retrovirology, Section, National Cancer
       Institute,; Bethesda, Maryland 20892.
 SO    Antimicrob Agents Chemother. 1994 May;38(5):1107-11. Unique Identifier :
       AIDSLINE MED/94346814
 AB    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.
 DE    Animal  Blood Proteins/METABOLISM  Cattle  Cells, Cultured  Human  HIV
       Protease Inhibitors/BLOOD/PHARMACOLOGY/*PHARMACOKINETICS  HIV-1/DRUG
       EFFECTS  Indicators and Reagents
       Oligopeptides/BLOOD/PHARMACOLOGY/*PHARMACOKINETICS
       Orosomucoid/METABOLISM  Protein Binding  Proteins/*PHARMACOLOGY
       Retroviridae/*DRUG EFFECTS  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).