A synthetic HIV-1 protease inhibitor with antiviral activity arrests HIV-like particle maturation.
A synthetic peptidemimetic substrate of the human immunodeficiency virus 1 (HIV-1) protease with a nonhydrolyzable pseudodipeptidyl insert at the protease cleavage site was prepared. The peptide U-81749 inhibited recombinant HIV-1 protease in vitro (inhibition constant Ki of 70 nanomolar) and HIV-1 replication in human peripheral blood lymphocytes (inhibitory concentration IC50 of 0.1 to 1 micromolar). Moreover, 10 micromolar concentrations of U-81749 significantly inhibited proteolysis of the HIV-1 gag polyprotein (p55) to the mature viral structural proteins p24 and p17 in cells infected with a recombinant vaccinia virus expressing the HIV-1 gag-pol genes. The HIV-1 like particles released from inhibitor-treated cells contained almost exclusively p55 and other gag precursors, but not p24. Incubation of HIV-like particles recovered from drug-treated cultures in drug-free medium indicated that inhibition of p55 proteolysis was at least partially reversible, suggesting that U-81749 was present within the particles.
Infectious Disease Research Unit, Upjohn Company, Kalamazoo, MI 49001.
T J
TJ
McQuade
A G
AG
Tomasselli
L
L
Liu
V
V
Karacostas
B
B
Moss
T K
TK
Sawyer
R L
RL
Heinrikson
W G
WG
Tarpley
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D004279:DNA, Viral / Q000235:genetics; D010450:Endopeptidases / Q000378:metabolism*; D015685:Fusion Proteins, gag-pol / Q000235:genetics / Q000378:metabolism; D015683:Gene Products, gag / Q000378:metabolism; D016333:HIV Protease; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000382:microbiology; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009842:Oligopeptides / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D004279:DNA, Viral; D015685:Fusion Proteins, gag-pol; D015683:Gene Products, gag; D009842:Oligopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D012367:RNA, Viral; C062520:U 81749; D010450:Endopeptidases; D016333:HIV Protease