Selective phosphinate transition-state analogue inhibitors of the protease of human immunodeficiency virus.
The phosphinic acid isosteres of di-, tetra- and hexapeptides containing a hydrophobic amino acid side chains at the P1-P'1 positions are powerful inhibitors of Human Immunodeficiency Virus protease. Ki's ranged from 0.4 nM to 26 microM at pH 6.5 and were lower at pH 4.5. The compounds showed no activity against trypsin, weak activity against renin at pH 6.5, moderate activity against pepsin at pH 2.0 (Ki values in the microM range) and substantial activity against cathepsin D at pH 3.5 (Ki values from 9 to 300 nM).
Grobelny
D
D
Department of Biochemistry, University of Kentucky, Lexington 40536.
Wondrak
E M
EM
Galardy
R E
RE
Oroszlan
S
S
D002402:Cathepsin D / Q000037:antagonists & inhibitors; D010450:Endopeptidases / Q000378:metabolism*; D004952:Esters; D015684:Gene Products, pol / Q000378:metabolism*; D016333:HIV Protease; D015497:HIV-1 / Q000201:enzymology*; D006863:Hydrogen-Ion Concentration; D009842:Oligopeptides / Q000494:pharmacology*; D010434:Pepsin A / Q000037:antagonists & inhibitors; D010721:Phosphinic Acids / Q000494:pharmacology*; D011480:Protease Inhibitors; D013329:Structure-Activity Relationship
D004952:Esters; D015684:Gene Products, pol; D009842:Oligopeptides; D010721:Phosphinic Acids; D011480:Protease Inhibitors; D010450:Endopeptidases; D016333:HIV Protease; D010434:Pepsin A; D002402:Cathepsin D