Peptide substrates and inhibitors of the HIV-1 protease.
Oligopeptides containing the consensus retroviral protease cleavage sequence Ser/Thr-X-Y-Tyr/Phe-Pro are substrates for purified recombinant HIV-1 protease with Km's in the millimolar range. The minimum sequence containing the consensus pentapeptide which serves as a good substrate is a heptapeptide spanning the P4-P3' residues. Substitution of reduced Phe-Pro or Tyr-Pro dipeptide isosteres or the statine analog 3-hydroxy-4-amino-5-phenylpentanoic acid for the scissile dipeptide afforded inhibitors of HIV-1 protease with Ki values in the micromolar range, three orders of magnitude better in affinity than the corresponding substrates. Inhibitors of HIV-1 protease may provide a novel and potentially useful therapeutic approach to the treatment of acquired immune deficiency syndrome (AIDS).
Moore
M L
ML
Department of Peptide Chemistry, Smith Kline & French Laboratories, King of Prussia, PA 19406.
Bryan
W M
WM
Fakhoury
S A
SA
Magaard
V W
VW
Huffman
W F
WF
Dayton
B D
BD
Meek
T D
TD
Hyland
L
L
Dreyer
G B
GB
Metcalf
B W
BW
D000595:Amino Acid Sequence; D010450:Endopeptidases / Q000378:metabolism; D016333:HIV Protease; D006868:Hydrolysis; D007700:Kinetics; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism*; D011480:Protease Inhibitors; D011994:Recombinant Proteins / Q000378:metabolism; D012191:Retroviridae Proteins / Q000378:metabolism; D013379:Substrate Specificity
D009842:Oligopeptides; D011480:Protease Inhibitors; D011994:Recombinant Proteins; D012191:Retroviridae Proteins; D010450:Endopeptidases; D016333:HIV Protease