In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine.
Transition state mimetic tripeptide human immunodeficiency virus (HIV) protease inhibitors containing allophenylnorstatine [(2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid] were synthesized and tested for activity against HIV in vitro. Two compounds, KNI-227 and KNI-272, which were highly potent against HIV protease with little inhibition of other aspartic proteases, showed the most potent activity against the infectivity and cytopathic effect of a wide spectrum of HIV strains. As tested in target CD4+ ATH8 cells, the 50% inhibitory concentrations of KNI-227 against HIV type 1 LAI (HIV-1LAI), HIV-1RF, HIV-1MN, and HIV-2ROD were 0.1, 0.02, 0.03, and 0.1 microM, respectively, while those of KNI-272 were 0.1, 0.02, 0.04, and 0.1 microM, respectively. Both agents completely blocked the replication of 3'-azido-2',3'-dideoxythymidine-sensitive and -insensitive clinical HIV-1 isolates at 0.08 microM as tested in target phytohemagglutinin-activated peripheral blood mononuclear cells. The ratios of 50% cytotoxic concentrations to 50% inhibitory concentrations for KNI-227 and KNI-272 were approximately 2,500 and > 4,000, respectively, as assessed in peripheral blood mononuclear cells. Both compounds blocked the posttranslational cleavage of the p55 precursor protein to generate the mature p24 Gag protein in stably HIV-1-infected cells. The n-octanol-water partition coefficients of KNI-227 and KNI-272 were high, with log Po/w values of 3.79 and 3.56, respectively. Degradation of KNI-227 and KNI-272 in the presence of pepsin (1 mg/ml, pH 2.2) at 37 degrees C for 24 h was negligible. Current data warrant further careful investigations toward possible clinical application of these two novel compounds.
Kageyama
S
S
Medicine Branch, National Cancer Institute, Bethesda, Maryland 20892.
Mimoto
T
T
Murakawa
Y
Y
Nomizu
M
M
Ford
H
H
Shirasaka
T
T
Gulnik
S
S
Erickson
J
J
Takada
K
K
Hayashi
H
H
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D004352:Drug Resistance, Microbial; D015683:Gene Products, gag / Q000378:metabolism; D006678:HIV / Q000187:drug effects* / Q000201:enzymology; D017320:HIV Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology; D015498:HIV-2 / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010654:Phenylbutyrates / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D015531:Radioimmunoprecipitation Assay; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; D015683:Gene Products, gag; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010654:Phenylbutyrates; D011498:Protein Precursors; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; C077823:kynostatin 227; D015215:Zidovudine; C034940:3-amino-2-hydroxy-4-phenylbutanoic acid; C077822:kynostatin 272