The evaluation of non-viral substrates of the HIV protease as leads in the design of inhibitors for AIDS therapy.
Scheme 1 summarizes some of what we have learned from this study of non-viral protein substrates of the HIV proteases. Many of these findings contradict the current understanding of protease specificity. P1-P1' amino acids need not be bulky or hydrophobic and residues at these positions may be even less important than those in flanking positions (e.g., Glu at P2') in dictating the course of hydrolysis. Thus, the pattern of amino acids over the whole binding region must be considered in predicting what will or will not be a substrate of these enzymes and, although we are beginning to understand selectivity at the level of primary structure, a detailed explanation of their specificity is yet to be forthcoming. Nevertheless, studies of this kind find useful application in the design of inhibitors of HIV proteases that will, hopefully, be of value in treatment of AIDS.
Tomasselli
A G
AG
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Hui
J O
JO
Sawyer
T K
TK
Thaisrivongs
S
S
Hester
J B
JB
Heinrikson
R L
RL
D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy*; D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism; D017320:HIV Protease Inhibitors; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000998:Antiviral Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D010455:Peptides; D011480:Protease Inhibitors; D016333:HIV Protease