Design and synthesis of HIV protease inhibitors. Variations of the carboxy terminus of the HIV protease inhibitor L-682,679.
A series of tetrapeptide analogues of 1 (L-682,679), in which the carboxy terminus has been shortened and modified, was prepared and their inhibitory activity measured against the HIV protease in a peptide cleavage assay. Selected examples were tested as inhibitors of virus spread in cell culture. Compound 12 was a 10-fold more potent enzyme inhibitor than 1 in vitro and 30-fold more potent in inhibiting the viral spread in cells.
deSolms
S J
SJ
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486.
Giuliani
E A
EA
Guare
J P
JP
Vacca
J P
JP
Sanders
W M
WM
Graham
S L
SL
Wiggins
J M
JM
Darke
P L
PL
Sigal
I S
IS
Zugay
J A
JA
D000998:Antiviral Agents / Q000138:chemical synthesis; D015195:Drug Design; D015683:Gene Products, gag / Q000032:analysis; D015488:HIV Antigens / Q000032:analysis; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000302:isolation & purification / Q000502:physiology; D006801:Humans; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D011498:Protein Precursors / Q000032:analysis; D013601:T-Lymphocytes / Q000382:microbiology; D014758:Viral Core Proteins / Q000032:analysis; D014764:Viral Proteins; D014779:Virus Replication / Q000187:drug effects; D054301:gag Gene Products, Human Immunodeficiency Virus
D000998:Antiviral Agents; D015683:Gene Products, gag; D015488:HIV Antigens; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011498:Protein Precursors; D014758:Viral Core Proteins; D014764:Viral Proteins; D054301:gag Gene Products, Human Immunodeficiency Virus; C054858:p17 protein, Human Immunodeficiency Virus Type 1; C059767:p55 gag precursor protein, Human immunodeficiency virus 1; C070944:L 682679